Triggering delay is the time interval between the initiation of the neural and mechanical inspiration [11,18]. If esophageal pressure (Pes) or EAdi monitoring is available, it is observed as the time elapsed between the reduction in Pes or increase in EAdi (start of neural inspiration) and the abrupt increase of flow or Paw (start of mechanical inspiration).

Ineffective efforts are patient’s efforts that fail to trigger the ventilator. Although usually described as a triggeringassociated dyssynchrony, ineffective efforts can happen at any time during the mechanical breath, during mechanical inspiration, expiration or at the transition between these two phases. The gold standard for their recognition is the simultaneous observation of the patient inspiratory activity. This is achieved either through recording of Pes or EAdi (Figure 2). Both methods are invasive and require the insertion of specified catheters: esophageal catheter, for Pes and NAVA catheter, for EAdi. In most cases, ineffective efforts can be identified non-invasively at the bedside, by observing the flow-time and Paw-time waveforms at the ventilator screen. Ineffective efforts cause distortions in the Paw and, more obviously, in the flow curve: an abrupt increase in inspiratory flow and a decrease in expiratory flow indicate the presence of ineffective efforts during mechanical inspiration and expiration, respectively (Figures 2 and 3) [11,18].

Triggering delay and ineffective efforts share common pathophysiological mechanisms. Their causes can be classified into two main categories: ventilator settings and patients’ characteristics [8,29-31]. Ventilator settings that predispose to triggering delay and ineffective efforts are the high assist level, the delayed opening of the expiratory valve and the low triggering sensitivity. These factors are determined by the physician. The main patients’ characteristics include low respiratory drive (i.e., sedation, central nervous diseases, etc.), weak inspiratory muscles (i.e., critical illness polyneuromyopathy, myasthenia, etc.), and high resistance and compliance that increase the time constant of the respiratory system.

The incidence and the magnitude of the delay of triggering and ineffective efforts are not minor in clinical practice. Ineffective efforts are the commonest form of patient-ventilator dyssynchrony. Vaporidi et al. [32] evaluated the role of ineffective efforts, specifically clusters of them, during MV on the outcome of critically ill patients. Events of ineffective efforts were identified in 38% of patients with prolonged MV and these events were associated with prolonged MV and increased mortality. Their incidence is higher in patients with obstructive lung disease [29,33]. In these patients, the low elastic recoil pressure and/or increased resistance increase the time required for the patient to exhale (high time constant), predisposing to air trapping and dynamic hyperinflation. Dynamic hyperinflation is the most important cause of triggering delay and ineffective efforts. In the presence of dynamic hyperinflation, an elastic threshold load (PEEPi) is imposed on the inspiratory muscles at the beginning of inspiration. The inspiratory muscles must first counterbalance PEEPi in order to decrease alveolar pressure below external positive end-expiratory pressure (PEEPe) and trigger the ventilator [34-36]. This creates a delay between the beginning of inspiratory effort and ventilator triggering. In severe cases of dynamic hyperinflation, especially if the effort is weak, the patient may fail to trigger the ventilator (ineffective effort). High airway resistance can be recognized in all ventilator modes by observing the expiratory flow-time curve. Early in expiration, a spike in expiratory flow signifies the dynamic compression of central airways [11]. Thereafter, the expiratory flow decreases but very slowly, if ever, returns to zero line before the following inspiration (Figures 2 and 3).

Delayed or missed triggers represent eccentric contractions of the diaphragm which may be deleterious for its function. They may cause distress and in their presence, the respiratory rate on the ventilator screen does not reflect the true respiratory rate of the patient. Strategies in order to reduce the triggering delay and the number of ineffective efforts should be investigated [8,11,22,29,31]. Firstly, ventilator settings should be revised. Setting the most sensitive triggering that does not cause autotriggering is an option. With regard to triggering sensitivity, it has been shown that the flow-waveform method [15], compared to flow triggering, enhances the sensitivity and thus reduces the incidence of these events. Furthermore, the newer methods for triggering in the context of Pdidriven servoventilation [20] and NAVA [21] eliminate these events. Ventilator settings that decrease dynamic hyperinflation and, hence, triggering delay and ineffective efforts are: (1) reduction of minute ventilation by lowering assist (decrease set pressure, set tidal volume) and respiratory rate decrease, (2) lengthening expiratory time through a higher flow threshold for cycling off and a faster rising time in pressure support or a higher inspiratory flow and a shorter plateau inspiratory pressure in assist volume control mode and (3) application of PEEPe. The PEEPe narrows the difference between the alveolar pressure and the threshold of pressure for the initiation of the mechanical inspiration, hence helping the patient to trigger the ventilator. This is especially helpful in some patients with severe obstructive lung disease [29,33]. Secondly, patient-related causes should be reviewed. Attention should be given in respiratory drive and the factors that may reduce it, such as excessive sedation and alkalemia. Efforts in order to decrease the magnitude of dynamic hyperinflation also should be done, in instance the use of corticosteroids, bronchodilating therapy and aspiration of secretions may result in reduced expiratory resistance.

Autotriggering occurs when the ventilator is triggered in the absence of patient effort [37,38]. This phenomenon can also be recognized by inspection of the ventilator waveforms. The absence of decrease in Pes (if it is monitored) or in Paw before the delivery phase, especially in the presence of a zero flow long enough before the mechanical breath, are signs that the breath is not triggered by the patient. The flow-time profile of the autotriggered breaths is, often, different from the corresponding of patient- triggered breaths (Figure 4). If secretions or cardiac oscillations are the cause, one might notice the associate flow distortion and suspect the phenomenon.

Autotriggering may be caused by a low threshold for triggering and/or artifacts that may cause a drop of Paw or flow, which is misinterpreted by the ventilator as patient effort. Artifacts that frequently cause autotriggering are circuit leaks, presence of water in the circuit, hiccups and strong cardiogenic oscillators [37,38]. Factors that predispose a patient to increased risk of autotriggering are the low respiratory drive and breathing frequency, the low time constant of the respiratory system (increased elastic recoil, low resistance) and the presence of hyperdynamic circulation (larger cardiac output and higher ventricular filling pressures).

Autotriggering is a common phenomenon during assisted modes of MV (invasive and non-invasive) [18,39]. When apparent, the respiratory rate is falsely elevated. These additional breaths may lead to hyperventilation, respiratory alkalosis, hyperinflation, and diaphragmatic dysfunction [2,40].

To eliminate autotriggering, the physician must try to correct the underlying cause: enhance the respiratory drive by reducing sedation, correct alkalosis by reducing the level of assist, aspirate secretions, and minimize circuit leaks. Moreover, a higher triggering threshold, or change from flow to pressure triggering may abolish autotriggered breaths [37,38].

When the exhalation valve of the ventilator opens too early, mechanical inspiration lasts shorter than neural inspiration. This form of dyssynchrony is often associated with insufficient support. Inspiratory muscle effort after the end of ventilator insufflation enhances the work of breathing and puts the patient at risk for double triggering. This asynchrony can present with the following ways [11]. (1) Zero or small inspiratory flow for some time after opening of the exhalation valve (Paw decreases to zero or PEEP level) indicates that inspiratory muscles continue to contract after the end of mechanical inspiration [41]. (2) A sharp decrease from the peak expiratory flow which lasts few milliseconds followed by an increase and then decreases gradually to zero toward the end of expiration: this pattern in the flow-time waveform is also a sign that considerable inspiratory muscle activity is present after opening of exhalation valve. When mechanical inspiration ends, end-inspiratory elastic recoil pressure is greater than inspiratory muscle pressure, creating positive alveolar pressure and, therefore, expiratory flow. Elastic recoil pressure decreases while lung volume declines due to inspiratory muscle contraction. An increasing opposing pressure to expiratory flow develops, causing an abrupt decrease in expiratory flow. This decrease is interrupted by the relaxation of the inspiratory muscles and expiratory flow increases and, therefore, follows the route as determined by the elastic recoil pressure and resistance of the patient and expiratory circuit [11]. (3) Double (or multiple) triggering: this refers to the delivery of two (or even more) ventilator insufflations during one single inspiratory effort. The inspiratory muscle contraction is great enough to overwhelm the elastic recoil pressure of the respiratory system and trigger the ventilator multiple times.

Premature cycling is associated with particular ventilator settings, such as low level of assist, relatively high threshold for cycling off and short inflation time. Short time constant of the respiratory system and long neural inspiration time are predisposing factors for this dyssynchrony. Furthermore, risk factors for multiple triggering are the low elastic recoil at the end of mechanical inflation and the intense inspiratory muscle activity [11,22].

As already mentioned, premature opening of the exhalation valve is related with increased work of breathing. Moreover, double triggering may provoke high tidal volumes (up to twice of the predetermined value) putting the patient at risk of ventilation-induced lung injury and ventilation-induced diaphragmatic dysfunction.

Premature opening of the expiratory valve and related multiple triggering can be minimized either by increasing the mechanical inspiration time and/or, if possible, by decreasing the neural inspiration time. The latter should be considered in patients with prolonged inspiratory efforts due to excessive administration of opioids. Actions that increase the mechanical inflation time include the lower flow threshold for cycling, the higher support and the slower rising time with pressure support mode [11,28]. With control modes, higher duration of mechanical inspiration should be easily achieved by proper adjustment of ventilator settings, such as inspiratory time, inspiratory flow or application of end-inspiratory pause [11,22].

When the exhalation valve opens too late, mechanical inspiration extends into neural expiration. This may promote rigorous expiratory muscle activity and increase the work of breathing as the patient struggles to terminate inspiration. Furthermore, it may unnecessarily increase the delivered tidal volume and shorten the available expiratory time. These effects may promote dynamic hyperinflation and associated dyssynchronies (delayed triggering, ineffective efforts), especially in patients with obstructive lung disease or provoke lung overdistention.

Recognition of the delayed opening of the exhalation valve is, often, challenging. During pressure support mode, it can be indicated by the fast decrease of the inspiratory flow followed by an exponential decline towards the end of mechanical inspiration [11]. An abrupt increase (spike) of the Paw near the end of mechanical inspiration is either a sign of inspiratory muscle relaxation or expiratory muscle contraction [42]. Whichever is the cause, this spike is an evidence of delayed cycling off (Figure 5). With assist-volume control ventilation, the sharp increase of Paw towards the end of mechanical breath indicates that mechanical inspiration is longer than neural.

Low flow threshold for cycling off, high support and low rise time are predisposing factors for this asynchrony during pressure support ventilation [43]. With assisted volume control mode, high tidal volume, increased inflation time, low inspiratory flow and application of end-inspiratory pause may causes delayed opening of the exhalation valve [43]. With pressure support mode, delayed opening of the expiratory valve is commonly observed in patients with long time constant of respiratory system, such as in patients with chronic obstructive lung diseases [44].

Independent of the mode of the ventilation, changes of the ventilator settings should be combined by measures that minimize the airway resistance and dynamic hyperinflation (i.e., bronchodilation, steroid therapy, aspiration of secretions).

Reverse triggering was first described by Akoumianaki et al. [45] who observed, in a group of heavily sedated

patients, the occurrence of patient inspiratory efforts that were triggered by the ventilator. This phenomenon, known as respiratory entrainment, has been previously described in animals, healthy subjects and preterm infants [40,46,47]. It differs from the other types of dyssynchronies in that the patient completely loses its normal breathing variability and actually breaths like a machine, exhibiting a fixed temporal relationship (1:1 or, less commonly, 1:2 or 1:3) between the onset of his inspiratory efforts and the onset of mechanical breaths. Vagal feedback and cortical influences are involved in the pathophysiological mechanism of these events [46,47]. Reverse triggered breaths may occur at any phase of the respiratory cycle and for variable periods. Their recognition, when Pes or EAdi recording is unavailable, is often difficult and requires careful inspection of the Paw- and flow-time waveforms (Figures 6 and 7). Depending on the phase of the mechanical breath that they occur, they may induce isometric or eccentric contractions of the respiratory muscles, augment the inflated tidal volume in pressure targeted modes or even trigger second breaths (breath stacking) causing hyperventilation and increasing the risk for lung overdistention (Figure 7) .

Inappropriate assist level (inadequate or excessive assist) with regard to patients’ ventilator demands is another cause of patient-ventilator dyssynchrony [11,22]. Inadequate assist level is usually observed in patients with high demands and increased respiratory drive (i.e., sepsis and metabolic acidosis). This discrepancy is combined with increased work of breathing and often the clinical status of the patient is indicative (i.e., use of accessory respiratory muscles, high respiratory rate).

Excessive assist level is often an outcome of low respiratory drive and/or inappropriate ventilator settings, but the adverse effects of this incompatibility are important. Dynamic hyperinflation, respiratory alkalosis, periodic breathing pattern due to lower apnoeic threshold, sleep disturbances, ventilator-induced diaphragmatic dysfunction and/or lung injury are potential consequences of high assist [44,48].

By inspecting the waveforms of Paw or flow, the respiratory effort in relation to assist level can be estimated [11,22]. Paw decreases when the inspiratory muscles contract and increases when the expiratory muscles contract. Paw is more sensitive in assist-volume control ventilation since it is the dependent variable. Although in pressure-targeted modes Paw should remain relatively constant, its shape may alter when the respiratory muscles contract rigorously (Figure 8). Furthermore, change in the flow pattern beyond the typical declining pattern is a sign of muscle effort [49]. Rapid decrease in inspiratory flow to flow threshold for cycling off in a patient with relatively long time constant is a sign of expiratory muscle contraction and thus a sign of high assist (Figure 9) [50]. Delayed cycling off might also indicate excessive assist. On the other hand, rounded or constant inspiratory flow represents significant inspiratory effort and might be due to insufficient assist (Figure 6). Supportive of insufficient assist is also the appearance of signs of premature cycling off or double triggering.