Optimizing the Patient Experience: Synchronized Human-machine Monitori

Patient-ventilator asynchrony is a major problem during noninvasive ventilation that can lead to discomfort and treatment failure. Therefore, identification and timely management of asynchronous abnormalities during noninvasive ventilation (NIV) in pediatric and adult populations is critical. In this review, we first define the different forms of asynchrony, their classification, and methods of quantification. Thus, we describe techniques to correctly detect patient-ventilator asynchrony during NIV in pediatric and adult patients with acute respiratory failure, respectively. Then, we describe measures that can be taken to reduce the occurrence of asynchrony, including the use of nontraditional ventilation patterns. Finally, we analyze the impact of asynchrony on clinical outcomes in infants, children, and adults as reported in the literature.

Presentation
Patients with acute respiratory failure (ARF) may benefit from different oxygenation or ventilation support . Noninvasive ventilation (NIV) plays an important role in patients with moderate to severe ARF, including cardiogenic pulmonary edema and slow-onset acute respiratory failure. However, NIV is affected by a certain percentage of treatment failures, mainly requiring transoral tracheal intubation and invasive mechanical ventilation.
Behind the type and severity of ARF, worsening gas changes, respiratory distress, hemodynamic instability, or worsening neurological function, NIV may also fail due to patient intolerance to therapy. Among the causes of treatment intolerance is the type of interface applied to the patient, the presence of large air leaks, and the occurrence of patient-ventilator dyssynchrony.
Patient-ventilator asynchrony remains a major problem during NIV in neonatal, pediatric and adult patients. In particular, patient-ventilator dyssynchrony can significantly increase respiratory effort and produce discomfort. Although the mechanisms behind these phenomena are well described, the impact of patient-ventilator asynchrony on clinical outcomes remains controversial.
Having defined the different types of asynchrony, we aimed to review the literature of the last 30 years on patient-ventilator asynchrony occurring during NIV in neonatal, pediatric and adult ARF patients. Our goal was to focus on the quantification, detection, management, and impact of asynchrony on clinical outcomes in patients receiving NIV.

Materials and Methods
Search strategy chosen for the study
The following search strategy was launched in PubMed on November 10: (("1992" [date - publication]: "2022" [date - publication]) AND ( "Patient - ventilator asynchrony" OR "Patient - ventilator interaction" OR "ineffective effort" OR "Wasted effort" OR "Auto-trigger" OR "Auto-trigger" OR "Double-trigger" OR "premature cycling" or "delayed cycling")).
After searching all references in published reviews to identify additional studies of interest that were missed in the primary search, both authors independently examined all articles and selected neonatal, pediatric, and adult ARF patients receiving NIV published in English between January 1, 1992, and November 1, 2022. In cases of disagreement, the expert opinion of a third reviewer was requested to make a decisive decision. Case reports, review articles, editorials, and studies that were available only in abstract form were excluded (Figure 1). Of the 585 records retrieved, 45 studies were included in the manuscript, and their references were searched for further titles.

Definition
An asynchronous event is a lack of coordination between the patient's respiratory activity and the mechanical assistance of the ventilator. During NIV, patient-ventilator asynchrony is classified as primary (invalid trigger, automatic trigger, and double trigger) and secondary (premature or early cycling, prolonged or delayed cycling, and delayed trigger), depending on the degree of coordination disturbance.

Ineffective triggering, also known as ineffective or wasted effort, is defined as the patient's ventilator-assisted inspiratory effort. This asynchrony may occur during the expiratory phase of the ventilator and during inspiratory ventilation assistance. Possible underlying mechanisms are thought to be weak respiratory drive and/or effort, high intrinsic positive end-expiratory pressure (PEEPi), and low ventilator trigger sensitivity .
Automatic triggering consists of mechanical air delivery that is not triggered by any inspiratory effort of the patient. This type of asynchrony is usually triggered by perturbations in airway pressure and/or flow or air leaks that are incorrectly perceived as triggering effort. Therefore, their occurrence depends largely on the type of trigger, sensitivity, and ability of the ventilator to compensate for air leaks.
Dual triggering is characterized by a single patient inspiration supported by two mechanical cycles and a very short expiratory time (<30% of the mean inspiratory time). Interrupting mechanical delivery before the patient's effort is complete produces a second triggered mechanical delivery after a brief expiratory phase.
Premature cycling is a form of patient-ventilator asynchrony characterized by interruption of ventilator delivery in anticipation of termination of patient effort; however, in the case of delayed cycling, mechanical assistance is longer than the patient's effort and extends into the patient's own (neural) expiration. Premature cycling is more frequent in patients with acute respiratory distress syndrome (ARDS) and may result in double triggering, whereas delayed cycling occurs more frequently in obstructive conditions. During NIV, delayed cycling is most often caused by air leaks, which prevent the expiratory trigger threshold from being reached and the air delivery cycle from closing.

Asynchrony Detection
The asynchronous rate is usually measured by the asynchronous index (AI%), defined by the ratio between asynchronous breaths and total breath counts, i.e., the sum of ventilatory cycles and non-triggered breaths, expressed as a percentage . In patients receiving invasive mechanical ventilation, AI% ≥ 10 was associated with worse clinical outcomes. Conversely, an AI% value ≥10 in patients receiving NIV was associated with poorer patient-reported comfort, but not with intubation rates, ICU length of stay, or mortality. Therefore, physicians should take steps to reduce the incidence of asynchronous events whenever the AI% value is ≥10 (see below).
Hinderby et al. also proposed an automated and standardized method to quantify asynchrony, the so-called Neural Synchronization Index. This index is based on the assessment and monitoring of electrical activity of the diaphragm (EAdi), which requires a dedicated catheter to be connected to a specific ventilator to obtain the diaphragm signal and offline analysis of the ventilator waveform to address asynchrony in rate problems. The neurosynchronous index was shown to be reproducible and correlated with manual analysis by experts.
Neonatal and Pediatric Patients
When high-flow oxygen therapy fails, NIV is considered the gold standard for treating neonatal, infant, and pediatric patients affected by ARF. Patient-ventilator asynchrony is a major challenge in non-adult patients, who are often evaluated using adjunctive EAdi signals to monitor diaphragmatic signals and respiratory effort. In 35 neonates and children receiving NIV pressure-supported ventilation (PSV) mode, Vignaux et al. reported a median AI% of 65. ineffective effort, automatic triggering, and premature cycling were the most common types of asynchrony. The authors also reported a significant reduction in median AI% to 40 after adjustment and optimization of ventilator settings. as recently reported, very preterm infants receiving conventional NIV modalities were characterized by a higher median AI% of up to 86%. In the pediatric population, the use of ancillary signals (e.g., EAdi) has been shown to improve the ability of pediatric intensivists to detect ineffective efforts and automatic triggers .
Adult Patients
In adult patients, patient-ventilator asynchrony has been assessed by a variety of methods, such as observation of waveforms on the ventilator screen, dedicated algorithms, or other signals (i.e., EAdi, esophageal or transdiaphragmatic pressure).
Visual inspection of ventilator waveforms is the most common method used in routine clinical practice. In fact, this method does not require the placement of any additional catheters, which can be considered difficult to locate and a source of further patient discomfort and air leaks. However, a multicenter study showed that the sensitivity of expert and non-expert physicians in detecting asynchrony during NIV by means of helmet or mask through separate ventilator waveform examination was very low. It is worth noting that the correct detection rate was inversely proportional to the prevalence of asynchrony.
Mulqueeny et al. developed an automated algorithm to detect ineffective efforts, such as expiratory flow perturbations without any ventilatory support and double triggering, because the interval between two mechanical ventilation inspiratory cycles was less than 500 ms. In 10 patients receiving PSV-mode NIV, the algorithm showed 95.1% specificity in detecting asynchrony. However, the algorithm has internal limitations and can only detect ineffective efforts during expiration and double triggering.
The NeuroSync Index proposed by Sinderby et al. is another automated algorithm tested in 12 patients with slow-plus acute respiratory failure during NIV.The NeuroSync Index ensures the correct detection of wasted effort during dedicated NIV ventilators or ICU ventilators equipped with leak compensation software and non-invasive neuromodulated ventilation assist (NAVA) provided by The NeuroSync Index ensures correct detection of wasted effort, triggered delays, and cyclic shutdown errors during PSV.
As previously mentioned, the algorithm requires positioning of the EAdi catheter, which somehow increases the cost and use of a dedicated ventilator equipped for EAdi monitoring and NAVA ventilation. Therefore, this system has inherent limitations that limit its application in all centers.
Recently, the application of diaphragmatic ultrasound has been proposed to identify patient-ventilator asynchrony during invasive mechanical ventilation. This technique was also tested on healthy volunteers who were receiving NIV and triggering asynchrony. The method involves monitoring diaphragm dome excursion or its thickening in the juxtaposition zone to determine the presence of respiratory effort in the patient. The septal ultrasound imaging is then coupled to the ventilator waveform in real time to identify and accurately identify asynchrony. It is important to note that although septal ultrasonography can be considered an "easy-to-learn technique, the need to visualize the airway pressure profile on the ultrasound machine screen limits its use in daily clinical practice. That said, whenever a ventilator waveform is screened on an ultrasound machine, this technique may play an important role in assessing patient-ventilator synchronization in the future.
Finally, electrical impedance tomography is a bedside lung function imaging tool that has been applied to the ARDS pig model to study the "oscillation" phenomenon when out of sync with the ventilator. With the exception of recent experimental use, no studies to date have evaluated ventilation or lung ventilation distribution in patients with invasive mechanical ventilation or severe NIV patient-ventilator asynchrony.

Asynchronous management
Neonatal and pediatric patients
In neonatal and pediatric patients, the management of human-machine asynchrony is critical. Because non-adult patients breathe up to 50 times/minute, optimal patient-ventilator synchronization allows for better unloading of the diaphragm.
In the case of patient-ventilator dyssynchrony, physicians should first evaluate ventilator settings and apply the interface. In fact, patient-ventilator synchronization is improved by adjusting the expiratory trigger settings during PSV. In addition, the presence of a large number of unexpected air leaks can also affect patient-ventilator synchronization. Therefore, changing the type of interface or adjusting its position should be considered. However, if these measures fail to reduce asynchrony, consider using an unconventional ventilation mode.NAVA is an unconventional ventilation mode driven by an EAdi signal that provides inspiratory assistance proportional to the EAdi, the closest recordable signal driven by the patient's central breathing. In particular, non-invasive NAVA has been shown to ensure optimal synchronization despite large air leaks or weak respiratory effort.
Adult patients
Unintentional air leaks are the most important source of asynchrony during adult NIV. The presence of large air leaks may create a special condition called "flow asynchrony". In fact, flow asynchrony is defined as an inconsistency between the ventilator flow output and the patient's inspiratory flow requirements. In intubated patients, flow asynchrony can increase work of breathing and respiratory distress. To control the occurrence of flow asynchrony, flow delivery must be optimized by adjusting the rise time, applying the NIV together with a dedicated ventilator equipped with leak compensation software, and reducing intentional and unintentional air leaks .
Therefore, selecting the appropriate interface, adjusting ventilator modes and settings, and using ventilators with leak compensation software can reduce the occurrence of man-machine asynchrony, including flow asynchrony
The selection of the NIV interface and the evaluation of its positioning should be one of the first actions implemented in the case of patient-ventilator asynchrony. When delivering NIV through a mask or bite port, the amount of air leakage varies considerably, with the higher the leakage, the higher the rate of asynchrony. Both masks and helmets as NIV interfaces increase the occurrence of asynchrony compared to invasive mechanical ventilation. Several studies have reported that helmets produce higher rates of asynchrony compared to masks. Because helmets suffer from internal deficiencies associated with large internal volumes and upward displacement during ventilator delivery, a new generation of helmets was developed to improve pressurization and patient-ventilator interaction. Compared to conventional helmets, the new helmet reduced inspiratory trigger delay, increased synchronization time between diaphragmatic activity and ventilator assist, and improved comfort overall. However, the recorded asynchronous events are similar between interfaces. Physicians should also minimize the number of air leaks, as these events can cause discomfort in and of themselves and are associated with asynchronous events.
Adjustment of ventilator settings and modes is another variable that can be corrected in the event of patient-ventilator asynchrony during NIV. Among the settings to be examined, high inspiratory pressure is associated with AI% >10%. In addition, individualized approaches should be used to address and set cyclic shutdown criteria to optimize synchronization with the ventilator and avoid "hang-ups".
In addition, the use of proportional ventilation modes such as proportional assist ventilation (PAV) or NAVA should be considered. Another study recently compared PAV and PSV in 15 patients with COPD exacerbation. PAV did not improve patient-ventilator interaction; moreover, the use of PAV+ (the development of PAV) triggered a loss of control, which could lead to asynchrony. The fact that PAV+ requires a closed system with no air leaks makes this mode no longer used during NIV.
In particular, while PAV requires the physician to set ancillary parameters (i.e., flow and volume assist) based on the patient's respiratory mechanics, PAV+ has implemented software to continuously monitor patient demand by measuring flow and volume every 5 ms and implementing short end-inspiratory occlusion. By requiring the physician to set only a load-adjustable gain factor, the ventilator will provide inspiratory support in proportion to the respiratory system's equation of motion. Thus, while air leaks do not impair the function of the pre-PAV mode, PAV+ requires a closed system to assess flow and volume and perform end-inspiratory occlusion.

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