Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: http://www.tandfonline.com/loi/ierx20

Recognizing, quantifying and managing patient-

ventilator asynchrony in invasive and noninvasive
ventilation

Eugenio Garofalo, Andrea Bruni, Corrado Pelaia, Luisa Liparota, Nicola

Lombardo, Federico Longhini & Paolo Navalesi

To cite this article: Eugenio Garofalo, Andrea Bruni, Corrado Pelaia, Luisa Liparota, Nicola
Lombardo, Federico Longhini & Paolo Navalesi (2018): Recognizing, quantifying and managing
patient-ventilator asynchrony in invasive and noninvasive ventilation, Expert Review of Respiratory
Medicine, DOI: 10.1080/17476348.2018.1480941

To link to this article: https://doi.org/10.1080/17476348.2018.1480941

Accepted author version posted online: 24

May 2018.

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Publisher: Taylor & Francis

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2018.1480941
Review

Recognizing, quantifying and managing patient-ventilator asynchrony in invasive and

noninvasive ventilation

Eugenio Garofalo1#, Andrea Bruni1#, Corrado Pelaia1, Luisa Liparota1, Nicola Lombardo2, Federico

Longhini3 and Paolo Navalesi*1

1
Anesthesia and Intensive Care, Department of Medical and Surgical Sciences, Magna Graecia

University, Catanzaro, Italy

2
Otolaryngology, Department of Medical and Surgical Sciences, Magna Graecia University,

Catanzaro,3Anesthesia and Intensive Care, Sant’Andrea Hospital, Vercelli, Italy.

#
Equal contributors

*Corresponding author:

Paolo Navalesi, MD, FERS

Dipartimento di Scienze Mediche e Chirurgiche

Università Magna Graecia

Viale Europa - Loc. Germaneto 88100

Catanzaro, Italy

Email: pnavalesi@unicz.it

Tel: +393355321910
ABSTRACT

Introduction: Patient-ventilator asynchrony may occur with modes of partial ventilatory

support. Because this problem is associated with worsened outcomes, identifying and

managing asynchronies has been recognized as a relevant clinical problem during both

invasive and non-invasive (NIV) mechanical ventilation.

Areas covered: In this review article, we first describe the different forms of patient-

ventilator asynchrony and how they are classified and quantified. Then, we show how these

asynchronies can be recognized, considering the techniques used to properly detect

asynchronies, by either ventilator waveform observation, or through systems based on more

complexes mathematical algorithms, by means of adjunctive signals, such as the electrical

activity of the diaphragm or esophageal pressure. Finally, we describe the actions that can be

undertaken in order to limit the rate of asynchronies during both invasive ventilation and NIV

mechanical ventilation, such as modifications of the ventilator mode and/or settings, variation

of the sedation regimen (type and doses), and other technical pitfalls.

Expert Commentary: Detection of asynchronies is crucial in order to reduce their incidence,

adopting adjustments of the ventilator settings, sedation regimen and other technical pitfalls.

It remains to be clarified whether the relationship between high incidence of asynchrony and

worsened outcome is causative or just associative.

Keywords: Mechanical ventilation, noninvasive ventilation, patient-ventilator interaction,

patient-ventilator asynchrony, ventilator waveforms, esophageal pressure, diaphragm

electrical activity, pressure support ventilation, neurally adjusted ventilatory assist,

proportional assist ventilation.

1.0 Introduction

Forms of partial ventilatory assistance are used to avoid complications and side effects of

controlled mechanical ventilation in patients with acute respiratory failure (ARF). These

modes offer advantages, such as reduced need for sedation, decreased risk of hemodynamic

impairment, respiratory muscles atrophy and dysfunction; however, poor patient-ventilator

interaction and synchrony may undermine these benefits, causing discomfort, agitation,

increased work of breathing and worsening of gas exchange [1].

Approximately one-fourth of patients receiving partial ventilatory assistance suffers of a

high incidence of asynchronies [2]. The negative impact of asynchronies on patients' outcome

has been known for 20 years. Chao et al. first observed that higher rates of patient-ventilator

asynchrony increased weaning failures [3]. Later on, other studies showed that, compared to

the patients displaying no or few asynchronies, those with asynchronous breaths exceeding

10% of the overall breath count were characterized by longer duration of mechanical

ventilation [2,4] and higher rate of tracheostomy [2]. More recently, Blanch et al.

demonstrated that patients with high rates of asynchronies are prone to higher intensive care

unit (ICU) and hospital mortality, and show a trend toward a longer duration of mechanical

ventilation [5].

Although it still unclear whether this relationship between asynchronies and poor

outcome is causative, i.e., asynchronies are responsible of the worsened outcome, or just

associative, i.e., patient-ventilator synchrony is a marker of severity of the sickest patient,

identifying and correcting for asynchronies has been increasingly recognized as a crucial

issue (Figure 1).

2.0 Definition and classification

The term "asynchrony" indicates, in general, disruption of coordination between two

events that are supposed to occur at the same time. When dealing with the interaction

between patient and ventilator, asynchrony commonly indicates a lack of coordination

between patient effort and ventilator assistance, which is the ventilator does not cycle in

unison with patient’s spontaneous breathing activity.

Different forms of asynchrony have also been classified with respect to the phase of the

respiratory cycle as 1) asynchronies of the triggering phase (i.e., ineffective efforts, auto-

triggering and triggering delay); 2) asynchronies during the delivery of inspiratory flow,

either during inspiration (too high or low inspiratory flow rate) and during expiration (i.e.,

double-triggering, premature or anticipated cycling, prolonged or delayed cycling) [6].

More recently, depending on the extent of the disturbance of coordination, patient-

ventilator asynchronies have been classified as 1) major (ineffective triggering, auto-

triggering and double-triggering); and 2) minor (premature or anticipated cycling, prolonged

or delayed cycling, triggering delay) [7]. The different forms of asynchronies are depicted in

Figure 2.

Ineffective triggering, also known as ineffective or wasted efforts, is by far the most

common form of major asynchrony and is characterized by an inspiratory effort not assisted

by the ventilator. It may occur during both the inspiratory or expiratory mechanical cycle, and

may depend on a variety of mechanisms, such as a weak respiratory drive and/or effort, a

high intrinsic positive end-expiratory pressure (PEEPì), an excessively low ventilator trigger

sensitivity [2,8-11].

Auto-triggering takes place when the ventilator delivers assistance unrelated to a patient’s

spontaneous effort. It occurs when the changes in airway pressure and/or flow secondary to

cardiac oscillations or air-leaks are erroneously sensed as triggering efforts [2,12]. Therefore,
their occurrence depends primarily on trigger type and sensitivity and, during noninvasive

ventilation (NIV), also on the ability of the ventilator to compensate for air-leaks [13].

Double-triggering, also named breath-stacking in Assist/Control (A/C) ventilation [14], is

characterized by two mechanical cycles triggered by the patient, separated by a very short

expiratory time (<30% of the mean inspiratory time) [2]. Double-triggering occurs because

the mechanical breath terminates before the completion of patient’s effort that, after a brief

exhalation phase, triggers a second mechanical breath [2,15]. Double triggering typically

ensues when patients with low respiratory system compliance receive Pressure Support

Ventilation (PSV) [16]; a high respiratory drive contributes to the development of this form

of asynchrony [2].

Premature cycling describes a condition where the end of the ventilator insufflation

anticipates patient’s effort termination, while, oppositely, delayed cycling denotes a condition

where the mechanical assistance exceeds patient’s own inspiration and extends into patient’s

own (neural) expiration. Premature cycling is more frequent in patients with low compliance,

such as Acute Respiratory Distress Syndrome (ARDS) patients [17-18] and may result [16] in

double triggering, while delayed cycling occurs more frequently in Chronic Obstructive

Pulmonary Disease (COPD) patients, who are characterized by high resistance and normal or

elevated lung compliance [8]. During NIV, by hindering achievement of the inspiratory flow

threshold determining insufflation cycling off, air-leaks also cause delayed cycling, which is

eliminated or at least reduced when the ventilator is equipped with a dedicated software for

air-leaks compensation [19]. Triggering delay indicates a prolonged time lag between onset

of patient's respiratory effort and commencement of ventilator support [20]. However, to our

knowledge, a threshold value defining the triggering delay is presently not available.

Very recently, some studies described a peculiar condition that cannot be comprehended

in the above classification, the reverse triggered breath, characterized by an inspiratory effort
apparently triggered by the ventilator. This phenomenon has been considered as a respiratory

entrainment (or respiratory phase locking), referring to an established fixed repetitive

temporal relationship between the neural and mechanical respiratory cycles [21].

3.0 Quantification of asynchronies

The rate of asynchrony is commonly measured by the Asynchrony Index (AI%), obtained

dividing the asynchronous breaths by the overall breath count, i.e. the sum of ventilator

cycles and non-triggered breaths, expressed as percentage [3]. Values of AI% is ≥10 are

characterized by prolonged duration of mechanical ventilation [2,5], increased rate of

weaning failure [3], higher tracheotomy rate [2], higher ICU and hospital mortality [5].

Worth remarking, the manner in which asynchronies are detected may significantly influence

the resulting AI%. Short of additional signals directly assessing patient’s respiratory effort,

such as esophageal pressure or diaphragm electrical activity (EAdi), the actual rate of

asynchrony is potentially underestimated [22]. Though to a lower extent, the same limitation

intervenes when computing the Ineffective Triggering Index (ITI), defined as the number of

ineffective efforts only divided by the total number of breaths (triggered and ineffectively

triggered) [10-11]. Higher ITI values have been reported with heavy sedations, especially

when consequent to propofol infusion [10-11].

Recently, Sinderby et al. proposed the NeuroSync Index, an automated, objective and

standardized method to assess patient-ventilator interaction and quantify asynchronies [23].

Based on EAdi continuous monitoring, the NeuroSync Index was found to be reproducible

and correlated to manual analysis by experts, and capable to assess patient-ventilator

interaction with more sensitive analysis than previous methods [23].

4.0 Detecting patient-ventilator asynchrony

4.1 Invasive ventilation

Patient-ventilator interaction is not guaranteed during invasive mechanical ventilation.

Chao et al. first observed, in an observational study conducted in a weaning center on 200

ventilator-dependent patients undergoing A/C ventilation through a tracheotomy, that

ineffective efforts, as assessed by esophageal pressure measurements, occurred in up to 10%

of the study participants [3]. Later on, Thille et al., in a cohort of 62 ICU patients receiving

either A/C or PSV, found that 24% of the patients undergoing partial ventilatory support had

an AI% ≥ 10%, considering just major asynchronies detected noninvasively by visual

inspection of flow and airway pressure signals [2]. Nowadays several studies have reported

an association between the incidence of asynchronies and a worsened patient outcome [2-3,5].

However, it has been shown that the incidence of asynchronies varies over the time; in

particular, ineffective efforts tend to occur in clusters between uneventful periods [5]. More

recently, clusters of ineffective efforts, as defined by the occurrence of more than 30

ineffective efforts in 3 minutes, while not an overall rate of ineffective triggering higher than

10%, were found to correlate with prolonged mechanical ventilation and increased mortality

[24]. However, it is still unclear if the high incidence of asynchronous events is just a marker

of illness severity of the patient, or a determinant for worsening of the final outcome, despite

the results of recent trials [25-26].

4.1.1 Adult patients

Currently, different modalities of asynchrony detection are employed during invasive

ventilation. The most important ones are based on the analysis of ventilator waveforms, as

well as on the use of specific software, assessment of EAdi, and measurement of esophageal

or transdiaphragmatic pressure.
 Bedside inspection of flow and airway pressure waveforms allows non-invasive

assessment of the asynchronies by the elementary observation track on the ventilator. With

this approach, some misclassification is expected. In fact, while double-triggering, i.e., two

pressurization separated by a very short expiratory time, is generally simple to recognize,

identifying whether or not a ventilator insufflation without a visible prior airway pressure

decrease is due to a brief and small inspiratory effort or caused by autotriggering is very

challenging. In the middle, ineffective efforts, recognized as by a drop of airway pressure

with a concomitant increase (if occurring during the expiratory phase) or decrease (if

occurring during the inspiratory phase) of airflow, are often, but not always, detectable by

this approach. Colombo et al. investigated the capability of ICU physicians to identify

patient-ventilator asynchronies through ventilator waveform inspection [22]. Two groups of

clinicians, composed by 10 experts (in staff for more than three years) and 10 non-expert

(residents) ICU physicians, were requested to analyze 43 5-minute reports from 24 patients

undergoing invasive mechanical ventilation in PSV mode. Overall, sensitivity and specificity

were 22% and 91%, respectively; sensitivity was significantly higher for expert (28%) than

for non-expert physicians (16%). Of note, the higher the prevalence of asynchronies, the

lower was the ability of proper detection [22].

Some studies proposed algorithms for automatic detection of asynchronies [27-30]. Chen

et al. developed a computerized algorithm to recognize and quantify ineffective efforts during

the expiratory phase, through the analysis of flow and airway pressure deflections [27]. They

reported that, in order to properly recognize ineffective efforts during the expiratory phase,

the optimal value for flow and airway pressure deflections differed among the 14 enrolled

patients. To generalize their results, they proposed optimal values for flow and airway

pressure deflections of 5.45 L/min and 0.45 cmH2O, respectively, which resulted in a good

accuracy, comparable to that obtained by visual assessment of esophageal pressure [27].

 Blanch et al. validated another algorithm, included in a dedicated software, that

automatically detects ineffective efforts during expiration through waveforms analysis [28].

In particular, this software calculates the theoretical expiratory flow curve of the patients and

computes the percent of deviation from the actual flow curve. If the deviation exceeds 42%,

the breath is considered an expiratory ineffective effort. The area under the curve (AUC) of

the receiving operating characteristics (ROC) curve was 0.964 (CI 95%, 0.952-0.975).

Notwithstanding the excellent performances, it is worth mentioning that both these

algorithms recognizes only ineffective efforts occurring during the expiration [27-28].

Mulqueeny et al. developed an algorithm to detect ineffective triggering and double

triggering [29]. This algorithm was tested in twenty patients undergoing PSV, ten invasively

and 10 noninvasively; when compared with visual inspection of transdiaphragmatic pressure,

in both conditions the algorithm resulted in a good accuracy, displaying both high sensitivity

and specificity [29].

Gutierrez et al. proposed airflow spectral analysis for detection of asynchronies, these

latter being characterized by a less organized spectral pattern [30]. The authors sampled flow

and airway pressure from 110 patients undergoing invasive mechanical ventilation during a

two-hour observation period and compared ability of the algorithm to detect AI% ≥ 10 with

values obtained by three trained observers analyzing flow and airway pressure. Both

sensitivity and specificity exceeded 80% [30], the major limitation being the comparison with

a gold standard potentially of limited validity [22,31].

Younes et al. described a method based on the equation of motion to identify non-

invasively onset and end of the inspiratory effort [32]. The authors proposed this approach to

improve patient-ventilator interaction and ventilator settings adjustments [32-33].

The use of adjunctive signals, such as the esophageal pressure or EAdi, greatly enhances

the chance to monitor patient-ventilator asynchronies. The use of esophageal (or

transdiaphragmatic) pressure guarantees a good estimation of patient’s inspiratory effort; it is,

nonetheless, semi-invasive and quite complex to accomplish, requiring placement of a

dedicated balloon-tipped catheter. Consequently, it is not routinely used in the clinical

practice for this purpose, representing, at the time being, a research tool.

EAdi monitoring also requires positioning of a dedicated nasogastric feeding tube, which

is connected to the ICU ventilator of a single manufacturer. EAdi waveforms are

continuously displayed on the ventilator screen with the conventional pneumatic signals, i.e.,

flow, volume and airway pressure [34].

Sinderby et al. proposed an automated index to evaluate patient-ventilator synchrony, the

NeuroSync Index (see above), based on simultaneous analysis of EAdi and the pneumatic

signals, which allows automated assessment of the time lag between neural efforts and

ventilator assist delivery [23]. The comparison of manual and automated detection methods

resulted in high test-retest and inter-rater reliability. The NeuroSync index increased the

sensitivity of detecting dyssynchronies, compared to previously published indices [23].

Rolland-Debord et al. conducted an ancillary study from data of a randomized controlled

trial, aimed at assessing the prevalence of patient-ventilator asynchrony according to two

methods of detection: manual analysis based on visual inspection of airflow and airway

pressure waveforms, and a computerized method combining EAdi with flow and airway

pressure signals analysis [35]. The first (manual) method resulted in a considerable

underestimation of the number of asynchronies (0.3/min), as opposed to the second one

(EAdi-based) (4.7/min) [35]. The AI% was, accordingly, underestimated by the first method

[35].

4.1.2 Neonatal and pediatric patients

Compared to adult patients, in newborns, infants and children the respiratory rate is
higher and the respiratory effort weaker, which make asynchronies more likely to occur [36].

In fact, several studies report a high rate of asynchronies with the conventional modes of

mechanical ventilation in these patients. In a recent prospective observational study

conducted in mechanically ventilated children from 0 to 18 years, the authors reported that

80% of patients had an AI% greater than 10%, ineffective efforts (68%), delayed cycling

(19%) and double triggering (4%) being the most commonly observed [37].

Because of this high incidence, detecting asynchronies would be of paramount

importance in the pediatric population. Surprisingly, however, studies exploring the ability of

physicians to detect asynchronous events by visually inspecting the waveforms displayed on

the ventilator screen lack, and the most commonly reported approach for detecting

asynchronies is the use of EAdi signal.

4.2 Noninvasive ventilation

NIV is a valuable ventilatory technique in several forms of ARF [38]. The success or

failure of NIV depends on several factors including the type and severity of respiratory

failure, the underlying disease, interface tolerance, hemodynamic instability, neurological

status deterioration and poor patient-ventilator interaction and synchrony [15,39-41]. In

particular, patient-ventilator asynchrony significantly contributes to increasing the work of

breathing [42-43], as well as causing discomfort [15,44]. In an observational study by

Vignaux et al., 26 out of 60 patients (43%) were reported to have an AI% ≥10%, as assessed

by surface diaphragmatic electromyography analysis [15].

4.2.1 Adult patients

Equally to invasive mechanical ventilation, the studies evaluating patient-ventilator

asynchrony during NIV adopt ventilator waveforms observation, or dedicated algorithms [29],
or additional signals to directly assess patient effort, such as EAdi, esophageal or

transdiaphragmatic pressure [20,45]. In routine clinical practice, visual inspection of the

ventilator screen is by far the commonest method adopted, as the placement of additional

catheters is source of further discomfort and potentially adds to air-leaks, and so far, to our

knowledge, no dedicated algorithm is commercially available for clinical use. Very recently,

however, a multicenter study evaluating the efficacy of this approach showed disappointing

results. Thirty-five ICU physicians in staff and 35 residents from Europe and China examined

flow and airway pressure tracings from 40 5-minute reports obtained by patients undergoing

NIV, delivered either by mask or helmet [7]. The overall median sensitivity and specificity

were 20% and 88%, respectively. The ability to detect asynchronies was better during NIV by

mask than by helmet, with no significant difference related to physician' s experience and

geographic provenience. Worth remarking, the rate of correct detection was inversely related

to the prevalence of asynchronies [7].

As already mentioned, the algorithm developed by Mulqueeny et al. showed a slight,

though significant, lower specificity during NIV (95.1%), as compared to invasive PSV

(99.1%), and did not considered asynchronies other than ineffective efforts and double

triggering [29]. The NeuroSync Index, proposed by Sinderby et al. [23], was tested in a

population of 12 patients with an acute exacerbation of COPD, for the purpose of evaluating

and comparing asynchronies during NIV delivered either by PSV with a dedicated NIV

ventilator, and PSV with an ICU ventilator equipped with a software for air-leaks

compensation, and NAVA (NIV-NAVA). Each trial lasted 30 minutes. The authors observed

that the automated analysis obtained by NeuroSync Index ensured a proper detection of

wasted efforts, triggered delays and cycling-off errors [46].

4.2.2 Neonatal and pediatric patients

As during invasive mechanical ventilation, patient-ventilator asynchrony is a relevant

problem for newborns, infants and pediatric patients receiving NIV. In an observational study

evaluating 35 newborns and children undergoing NIV in PSV mode, Vignaux et al. reported a

median AI% of 65, that decreased to 40 when the ventilator settings were adjusted at their

best. The three most frequent asynchronous event were autotriggering, ineffective efforts and

premature cycling [36].

4.2.3 Long term ventilation

Long term noninvasive ventilation (NIVLT) is frequently used for treatment of chronic

respiratory failure of different etiologies, including neuromuscular diseases, restrictive chest-

wall disorders, obesity-hypoventilation syndrome and COPD [47]. Some studies show that

patient-ventilator asynchrony is common in NIVLT. Fanfulla et al. reported that a high

incidence of ineffective efforts during NIVLT was associated with a poorer nocturnal oxygen

gas exchange [48]. Ramsay et al. used parasternal electromyography to assess both type and

prevalence of asynchrony occurring during NIVLT [49]. They observed that nearly 80% of

patients had an AI% ≥10. Overall, ineffective efforts were the most common asynchrony,

while autotriggering had a higher prevalence in COPD patients. In contrast to the previously

quoted study, however, no correlation was found between asynchrony and overnight oxygen

saturation and transcutaneous carbon dioxide [49].

Cuvelier et al. described the performance of an algorithm based on analysis of the

ventilator tracings aimed to ascertained properly or ineffectively triggered ventilator cycles

[50]. They enrolled 14 children affected by cystic fibrosis in NIVLT and assessed if this

algorithm could correctly detect triggered and non-triggered cycles. The authors found that

the algorithm correctly identified 100% of triggered cycles and 94.6% of ineffective
triggering efforts [50]. In keeping with the remarks made about similar software for

automated analysis of asynchrony in adult patients [29], this algorithm is also limited to

ineffective triggering [50].

5.0 Managing patient-ventilator asynchrony

5.1 Invasive ventilation

5.1.1 Adult patients

Chao et al. first described that reducing the amount of ventilator-delivered volume

decreases the rate of ineffective triggering by augmenting patient’s inspiratory effort, thus

identifying over-assistance as a major determinant of this type of asynchrony [3]. Thille et al.

confirmed this observation in a series of patients undergoing PSV through an endotracheal

tube, reporting that decrementing the inspiratory pressure support from 20 to 13 cmH2O

significantly reduced tidal volume and, concomitantly, the rate of ineffective efforts, without

inducing signs of poor tolerance or dyspnoea [51].

In a mixed population of ICU patients, Colombo et al. increased and decreased by 50%

the ventilatory support. When reducing the assistance, tidal volume remained unchanged and

patient effort, as assessed by EAdi, raised up, while augmenting support determined an

increase of tidal volume associated with a reduction of EAdi, resulting in a higher rate of

ineffective efforts [52].

Reducing tidal volume and minute ventilation also improves, especially in patients with

airway obstruction, patient-ventilator synchrony by decreasing auto or intrinsic positive end-

expiratory pressure (PEEPi), which leads to ineffective triggering [51]. In patients with acute

asthma and acute on chronic obstructive pulmonary disease (COPD), reducing airways

resistance by delivering bronchodilators reduces PEEPi and is therefore potentially helpful to

contain ineffective efforts [53]. When PEEPi is associated with expiratory flow limitation as
it is commonly the case in the course of a COPD exacerbation, judicious application of

external PEEP facilitates ventilator triggering by patient’s effort, eliminating or limiting

ineffective triggering [54].

Inspiratory and expiratory trigger threshold settings are also crucial determinant of

optimal patient-ventilator synchrony. While on the one hand a high inspiratory trigger

threshold prevents the patient from triggering the ventilator, an excessively low threshold

results in autotriggering, when small flow and pressure variations due to the cardiac

oscillations become sufficient to trigger the ventilator [12]. Other sources of pressure or flow

distortion may determine autotriggering, such as leakages or water accumulated in the in the

circuit. The expiratory trigger threshold during PSV is also an important determinant of

patient-ventilator synchrony. In intubated patients receiving PSV, Tassaux et al. evaluated a

mathematical model to adjust the optimal level of expiratory trigger threshold and found that

the expiratory trigger should be accurately titrated according to the respiratory system

mechanics determining the time constant, and magnitude and duration of the inspiratory

effort [55].

By altering the respiratory drive and timing, sedative and analgesic drugs affect patient-

ventilator interaction and may give rise to asynchronies. In 20 patients admitted to a medical

ICU, De Wit et al. showed that deep levels of sedation were associated with an increased

incidence of ineffective efforts [11]. However, they did not assess the specific effect of single

drugs. Vaschetto et al. investigated the effects of different depths of propofol sedation in

fourteen intubated patients undergoing both PSV and Neurally Addjusted Ventilatory Assist

(NAVA) [10]. Propofol significantly reduced the respiratory drive and effort to an extent that

varied with the rate of infusion. In particular, heavy sedation significantly depressed the

respiratory drive and deteriorated patient-ventilator synchrony during PSV, but not during
NAVA; lower doses of propofol such to determine light sedation produced less relevant

effects on synchrony [10].

In 13 intubated patients, Costa et al. studied the effects of incremental doses of opiods on

breathing pattern, respiratory drive and patient-ventilator interaction during both PSV and

NAVA [56]. Incremental doses of remifentanil produced progressive prolongation of the

neural expiratory, which resulted in a parallel reduction of respiratory rate. The effect on the

respiratory drive, as assessed by EAdi, was minor, with unimportant consequences on

patient-ventilator synchrony, irrespective of the mode of ventilation [56].

Conti et al. observed for 24 hours 20 difficult-to-wean patients randomized to receive

either dexmedetomidine or propofol to maintain the Richmond Agitation Sedation Scale

(RASS) between +1 and -2 [57]. Compared to light propofol sedation, dexmedetomidine

resulted in non-significantly higher EAdi (from 20% to 50% at the different time points) and

slightly fewer asynchronies statistically significant only at 12 hours [57]. Hence,

dexmedetomidine, remifentanil and low doses of propofol can be used to alleviate discomfort,

pain and anxiety, without producing major effects on patient ventilator synchrony, while

deeper levels of sedation with propofol determine reductions in respiratory drive potentially

affecting patient-ventilator synchrony.

Chanques et al. compared, in 254 patients undergoing A/C ventilation, three strategies,

i.e., no intervention, modifications of sedation-analgesia or changes of ventilator setting, in

order to reduce breath-stacking asynchrony. In 66 patients who showed severe asynchrony, as

indicated by an AI% ≥10, modifying the ventilator settings was found to be more effective in

reducing the rate of asynchrony than varying analgo-sedation practices [14].

A further challenging approach to improve patient-ventilator synchrony is matching

ventilator support to ventilator demand. For this purpose, two modes of mechanical

ventilation, referred to as proportional modes, are presently available for intubated patients,
Proportional Assist Ventilation (PAV) and NAVA. PAV is a mode of ventilation that

instantaneously delivers inspiratory support in proportion to patient's generated flow (flow

assist) and volume (volume assist). Therefore, at an increased effort resulting in an

augmented ventilatory output corresponds an increased support delivered by the ventilator.

Because for properly setting PAV it is fundamental to know respiratory system resistance and

elastance [58], it is presently available in an automated version periodically reassessing

respiratory mechanics (PAV+). Compared to PSV, PAV and PAV+ improve patient-

ventilator interaction and synchrony [59-60] by reducing the risk of over-assistance. The

inspiratory trigger, however, is flow-regulated, as in the conventional ventilatory modes.

NAVA has the unique feature of controlling ventilator functioning through a non-

pneumatic signal, EAdi, as assessed by transesophageal electromyography obtained by means

of a dedicated feeding tube mounting a distal array of multiple electrodes [34]. The

microvolts of EAdi are multiplied by a user-controlled gain factor, the NAVA level, whose

unit is cmH2O/microvolt. The airway pressure applied by the ventilator depends on the

magnitude of both EAdi and NAVA level. In NAVA, the mechanical support is on- off-

triggered by the EAdi and is proportional to EAdi throughout inspiration, varying breath-by-

breath in proportion to EAdi. Several studies have reported that NAVA is able to assure an

optimal patient-ventilator synchrony as opposed to PSV [25,34,52,61]. A recent randomized

controlled trial confirmed the improved synchrony with NAVA as opposed to PSV but failed

to show associated improvement of clinical outcomes such as time spent on mechanical

ventilation, ICU and hospital lengths of stay and mortality [25].

5.1.2 Neonatal and pediatric patients

Several studies have recently investigated the application of NAVA in particular in

preterms and neonates, all reporting an improvement of patient-ventilator synchrony during

NAVA, as compared to conventional modes [62-63].

Worth mentioning, also in the pediatric population no study demonstrated a causative

relationship between asynchrony and worsened outcome.

5.2 Noninvasive ventilation

5.2.1 Adult patients

In NIV air-leaks represent the major source of asynchrony [15,19]. The development of

software capable to detect and compensate for air-leaks has greatly enhanced patient-

ventilator interaction during NIV, lowering the occurrence of auto-triggering, ineffective

efforts, and late cycling, while not of premature cycling [64]. Recent work comparing

standard PSV mode with NIV-mode of six ICU ventilators decreased mean AI% from 31 to

14.5, ineffective efforts and delayed cycling being the most recurrent asynchronies [65].

Surprisingly, Carteaux et al. did not confirm significant AI% differences between ICU

ventilators, with or without NIV software, while found that AI% was significantly lower

when a dedicated NIV ventilator was used [66].

Ventilator settings are also important determinant of asynchrony. In particular, high levels

of inspiratory pressure are associated with increased AI% ≥10% (OR: 1.32 per additional cm

H2O of pressure support, 95% CI: 1.10-1.58; p=0.003) [15]. The expiratory trigger threshold

also plays a role. A bench study performed by Moerer et al. showed that an individualized

approach for cycling-off criterion should be considered, in order to optimize synchronization

with the ventilator [67]. Physicians should also minimize the number of air-leaks, because

these events caused discomfort by themselves, and were also shown to be associated with an
increased ratio of asynchrony (OR: 1.24 per additional l/min of leak, 95% CI: 1.03-1.48;

p=0.019) [15].

As for invasive mechanical ventilation, the proportional modes might improve patient

ventilator interaction. Unfortunately, although a few studies evaluated patient comfort and

tolerance, which may be affected by synchrony, no study has directly assessed patient-

ventilator synchrony with PAV for comparison with other modes. In a randomized pilot

study by Gay et al. in patients with mild to moderate ARF receiving NIV, PAV was found

to be better tolerated by patients, when compared to conventional PSV mode. Noteworthy,

however, PAV and PSV were delivered by two distinct ventilators, of which only the

machine used to deliver PAV was equipped with a software for air-leak compensation [68].

A larger prospective randomized single-center trial compared PSV and PAV during NIV in

117 patients with ARF of varied aetiologies, in order to assess the differences in the rates of

death and intubation (primary outcome), and other secondary outcomes, including comfort

[69]. Although the major clinical outcomes were unaffected by the ventilatory mode,

comfort resulted to be significantly improved by PAV, as opposed to PSV [69]. Indeed,

during non-invasive PAV, air-leaks hinder the exhalation because the ventilator keeps

being pressurized consequent to support delivered in relationship to the leaked flow and

volume, making impossible its use without a highly efficient software for detection and

compensation of air-leaks. PAV+ requires a perfectly closed system and thus is not

applicable for NIV. As a matter of fact, this mode PAV is no longer used for NIV

application.

Quite the opposite, not using any pneumatic signal for triggering, delivering and

interrupting the ventilator assistance, NAVA is ideal for NIV. Cammarota et al. first

compared NAVA and PSV during NIV by helmet in a population of patients with post-

extubation hypoxemic ARF [20]. Compared with PSV, NAVA had shorter inspiratory trigger
delay and longer time of synchrony between neural effort and ventilator support.

Furthermore, an AI% ≥10 never occurred in NAVA, in contrast to PSV (80% of trials).

Arterial blood gases were no different between the two modes [20]. These findings were later

confirmed by several studies where NIV was delivered by mask [70-72]. In a series of

patients with ARF or at risk of post-extubation respiratory failure, Piquilloud et al. also found

that trigger delays and asynchronies significantly improved with NAVA, compare to PSV

[70]. Breathing pattern and arterial blood gases were similar with the two modes [70].

Schmidt et al. compared PSV and NAVA, both applied with or without automatic air-leaks

compensation, in a population of patients receiving post-extubation prophylactic NIV [71].

Compared to PSV, NAVA improved patient-ventilator interaction and synchrony, regardless

of the NIV algorithm [71]. Of note, the algorithm for air-leaks compensation significantly

reduced the incidence of asynchronous events during PSV, while not in NAVA [71]. A

further study performed in a population of patients with ARF of various etiologies confirmed

the improvement of patient-ventilator interaction and synchrony with the use of NAVA, as

opposed to PSV [72]. Very recently, a new setting of NAVA for NIV, defined neurally

controlled pressure support (PSN), has been described and compared with NAVA and

conventional pneumatically-regulated PSV (PSP), during NIV delivered by helmet [73] and

mask [74]. PSN was obtained increasing NAVA level at the maximum level and setting an

upper airway pressure limit [73-74]. Compared to PSP, the neutrally triggered modes (NAVA

and PSN) improved patient-ventilator interaction and synchrony. Furthermore, by optimizing

pressurization and triggering performance, PSN improved comfort, as opposed to both PSP

and NAVA [73-74].

Patient-ventilator interaction is also affected by the interface. Costa et al. assessed in

bench the performance of the endotracheal tube, the face mask and the helmet, reporting that

the occurrence of asynchronies was significantly lower with the tube than with both
noninvasive interfaces [75]. Nonetheless, the helmet was characterized by worsened

synchrony, compared to the mask [75]. Fraticelli et al. compared four interfaces, a

mouthpiece, one integral (total full-face) and two oral-nasal masks. The three masks showed

less air-leaks, fewer asynchronies and better comfort, compared to the mouthpiece [76]. In a

head-to-head comparison between helmet and facial mask in patients with COPD, Navalesi et

al. found the former to be characterized by much larger trigger delays and higher rates of

ineffective efforts, although both interfaces improved inspiratory effort and gas exchange

[77]. In order to improve the loose patient-ventilator interaction repeatedly observed with the

conventional helmet, a new helmet has been recently proposed, which is free of armpit braces

and reduces the helmet upward displacement during ventilator insufflation, thereby

improving pressurization. Olivieri et al. recently confirmed in ICU patients the positive

results obtained by this new device on bench [78] and in healthy volunteers [79], reporting

that, compared to the standard helmet, this new helmet reduced the inspiratory trigger delay,

increased the time of synchrony between diaphragm activity and ventilator assistance, and

overall improved comfort [80].

5.2.2 Neonatal and pediatric patients

For managing asynchronies in pediatric patients, non-invasive NAVA guarantees an

optimal synchronization despite large air-leaks through the interfaces and weak respiratory

efforts [63,81]. Vignaux et al. showed that adjusting the expiratory trigger settings in PSV

improved patient-ventilator synchrony, which was, nonetheless, further remarkably enhanced

when NAVA ventilation was instituted [36].

5.2.3 Long term ventilation

In order to reduce the rate of asynchrony during NIVLT, the device for NIVLT delivery and

the ventilator settings should be carefully selected. Recently, Zhu et al. tested on a bench

model the performance of three home ventilators, thus demonstrating that new flow-based

triggering algorithms were able to improve trigger sensitivity and decrease the impact of

unintentional leaks, thereby reducing ineffective efforts and autocycling [82]. Adler et al.

showed that guiding ventilator setting adjustments by polysomnography during nocturnal

NIV lowered patient-ventilator asynchrony, as defined by the ratio between sleep time spent

with ineffective efforts and total sleep time [83]. In addition, this approach was able to

improve patient comfort, morning dyspnea, air-leaks and overall quality of sleep [83]. In

order to identify the optimal strategy to reduce patient-ventilator asynchrony in stable

hypercapnic COPD patients on NIVLT, Duiverman et al. evaluated four ventilatory settings

characterized by varying inspiratory positive airway pressure (IPAP) and backup respiratory

rate [84]. They observed that the prevalence of trigger asynchronies was higher during high-

pressure, low-rate NIV (IPAP >25 and ≤34 cmH2O; backup rate 10 breaths/min), whereas

high-intensity NIV, as defined by the application of higher IPAP and backup rate, did not

increase patient-ventilator asynchrony, while reducing respiratory muscle activity [84].

6.0 Conclusions

Clinically relevant asynchronies are common both in invasive ventilation and NIV. Patient-

ventilator asynchrony occurs not only in critically ill adults, but also in pediatric patients and

in long-term treatment for severe chronic stable hypercapnic respiratory. Detection of

asynchronies by ventilator waveforms observation is problematic. Dedicated software for

automatic detection of asynchronies or adjunctive signals, such as esophageal pressure or

EAdi, are helpful for proper detection. Patient-ventilator synchrony can be improved by
proper adjustments of the ventilator settings, cautiously administering analgesic and sedative

drugs to avoid over-sedation, and using when possible the proportional ventilatory modes.

High rates of asynchrony are associated with worsened patients' outcomes. However, it

remains to be demonstrated whether or not this relationship is causative.

7.0 Expert commentary

Patient-ventilator asynchrony is reported in approximately one-fourth of patients receiving

partial ventilatory assistance through an endotracheal tube, and up to 80% of patients

receiving non-invasive ventilation (NIV). Depending on the extent of the disturbance of

coordination, patient-ventilator asynchronies can be classified as major (ineffective triggering,

auto-triggering and double-triggering), and minor (premature or anticipated cycling, and

prolonged or delayed cycling).

The rate of asynchrony is commonly measured by the Asynchrony Index (AI%), obtained

dividing the asynchronous breaths by the overall breath count, i.e. the sum of ventilator

cycles and non-triggered breaths, expressed as percentage. Values of AI% ≥10 are considered

clinically relevant. In fact, values of AI% ≥10 are associated with worsened patient outcomes,

such as increased weaning failures, longer duration of mechanical ventilation, higher rate of

tracheostomy, higher intensive care unit (ICU) and hospital mortality. High rates of patient-

ventilator asynchrony are reported also in the pediatric population and in patients on long-

term NIV for management of chronic stable hypercapnic respiratory failure.

Poor patient-ventilator interaction leading to asynchrony causes discomfort, agitation,

increased work of breathing and worsening of gas exchange. Therefore, detecting and

managing asynchronies is nowadays considered a key point for mechanically ventilated

patients. Visual inspection of flow and airway pressure waveforms allows non-invasive

assessment of asynchronies by the elementary observation track on the ventilator. Although

this approach offers advantages such as being applicable at bedside and not necessitating

additional means, it has been shown to be problematic for correct recognition of asynchronies,

during both invasive ventilation and NIV. Dedicated software with specific computerized

algorithms have been developed for this purpose, but, to our knowledge, none of them has

been implemented for clinical use in commercially available devices.

Several strategies are helpful in order to reduce asynchronies. First of all, over-assistance

should be avoided. Lessening the inspiratory support decreases the rate of ineffective

triggering by increasing patient respiratory drive. Also, reducing tidal volume and minute

ventilation improves patient-ventilator synchrony, especially in patients with airway

obstruction, by decreasing auto or intrinsic positive end-expiratory pressure (PEEPi), another

determinant of ineffective triggering. By matching ventilator support to patient’s ventilatory

demand the proportional ventilatory modes, namely Proportional Assist Ventilation (PAV)

and Neurally Adjusted Ventilatory Assist (NAVA) avert the risk of over-assistance. They are

both effective in improving patient-ventilator interaction and decrease the rate of asynchrony

in invasive ventilation, while only NAVA can be applied in NIV. Inspiratory and expiratory

trigger threshold settings have also been shown to be crucial determinant of optimal patient-

ventilator synchrony. For example, excessively low trigger threshold may cause

autotriggering, consequent to small flow and pressure variations due to cardiac oscillations

sufficient to trigger the ventilator. Quite the opposite, high inspiratory trigger thresholds may

result in ineffective triggering. The expiratory trigger threshold during PSV is also an

important determinant of patient-ventilator synchrony and should be titrated according to the

respiratory system mechanics and duration of the inspiratory effort.

By altering the respiratory drive and timing, sedative and analgesic drugs affect patient-

ventilator interaction and may give rise to asynchronies. Though these effects are drug-
dependent and dose-dependent, over-sedation should be avoided. Finally, in patients

undergoing NIV, it is crucial choosing the right interface to avoid excessive air-leaks.

8.0 Five-year view

While the knowledge about mechanisms, detection and managements of asynchronies has

remarkably increased in the last decade, it remains to be clarified whether the relationship

between high incidence of asynchrony and worsened outcome is causative or just associative.

Future research should be addressing this issue.

Key issues:

 Asynchronies are events characterized by lack of coordination between patient's

respiratory effort and ventilator assistance.

 Clinically relevant asynchronies are present in up to 25% of patients undergoing

invasive mechanical ventilation, and up to 60% of those receiving noninvasive ventilation.

 Rates of asynchrony equal to or higher than 10% are associated with worsened

patients' outcomes.

 Detection of asynchronies by ventilator waveforms observation is problematic in

some instances.

 Dedicated software for automatic detection of asynchronies or adjunctive signals,

such as esophageal pressure or electrical activity of the diaphragm, are helpful for proper

detection.

 Patient-ventilator synchrony can be improved by choosing apt modes of ventilation,

adjusting the ventilator settings, cautiously administering analgesic and sedative drugs to

avoid over-sedation, and providing treatments aimed at improving patients' respiratory

mechanics.
  Patient-ventilator asynchrony is a major issue not only in critically ill adults, but also

in pediatric patients and in patients with severe chronic stable hypercapnic respiratory

failure receiving long-term non-invasive ventilation.

Funding

This paper was not funded.

Declaration of interest

P Navalesi contributed to the development of the helmet Next (Castar Next, Intersurgical,

Mirandola, Italy), whose license for the patent belongs to Intersurgical S.P.A., and received

royalties for that invention. P Navalesi’s research laboratory has received equipment and/or

grants from Maquet Critical Care, Intersurgical S.p.A., and Draeger Medical GmbH. They

also report receiving honoraria/speaking fees from Maquet Critical Care, Hillrom, Orion

Pharma GmbH, Resmed and Philips. The authors have no other relevant affiliations or

financial involvement with any organization or entity with a financial interest in or financial

conflict with the subject matter or materials discussed in the manuscript apart from those

disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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Figure 1. Studies published on patient-ventilator asynchrony from 1997 to 2017. The studies

are shown as a whole and divided according to the subjects evaluated, i.e., adult

(black), pediatric (gray) and animal-bench (white). The amount of studies published

in adult and pediatric patients has remarkably increased in the last decade.
Figure 2. From top to bottom, waveforms of airway pressure (Paw), flow and Electrical

Activity of the Diaphragm (EAdi) are depicted for each type of patient-ventilator

asynchronies (see text). Arrows highlight the asynchronous events. Triggering delay

is pointed out also by the two dashed lines.