de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 https://doi.org/10.1186/s40635-019-0234-5 Intensive Care Medicine Experimental REVIEW Open Access Patient-ventilator asynchronies during mechanical ventilation: current knowledge and research priorities Candelaria de Haro1,2* , Ana Ochagavia1,2, Josefina López-Aguilar1,2, Sol Fernandez-Gonzalo1,3, Guillem Navarra-Ventura1, Rudys Magrans1,2, Jaume Montanyà4, Lluís Blanch1,2 and the Asynchronies in the Intensive Care Unit (ASYNICU) Group From The 3rd International Symposium on Acute Pulmonary Injury Translational Research, under the auspices of the: ‘IN- SPIRES®' Amsterdam, the Netherlands. 4-5 December 2018 * Correspondence: cdeharo@tauli. cat Abstract 1 Critical Care Center, Hospital Universitari Parc Taulí, Institut Background: Mechanical ventilation is common in critically ill patients. This life- d’Investigació i Innovació Parc Taulí saving treatment can cause complications and is also associated with long-term I3PT, Universitat Autònoma de sequelae. Patient-ventilator asynchronies are frequent but underdiagnosed, and they Barcelona, Parc Taulí 1, 08208 Sabadell, Spain have been associated with worse outcomes. 2 CIBERES, Instituto de Salud Carlos Main body: Asynchronies occur when ventilator assistance does not match the III, Madrid, Spain Full list of author information is patient’s demand. Ventilatory overassistance or underassistance translates to different available at the end of the article types of asynchronies with different effects on patients. Underassistance can result in an excessive load on respiratory muscles, air hunger, or lung injury due to excessive tidal volumes. Overassistance can result in lower patient inspiratory drive and can lead to reverse triggering, which can also worsen lung injury. Identifying the type of asynchrony and its causes is crucial for effective treatment. Mechanical ventilation and asynchronies can affect hemodynamics. An increase in intrathoracic pressure during ventilation modifies ventricular preload and afterload of ventricles, thereby affecting cardiac output and hemodynamic status. Ineffective efforts can decrease intrathoracic pressure, but double cycling can increase it. Thus, asynchronies can lower the predictive accuracy of some hemodynamic parameters of fluid responsiveness. New research is also exploring the psychological effects of asynchronies. Anxiety and depression are common in survivors of critical illness long after discharge. Patients on mechanical ventilation feel anxiety, fear, agony, and insecurity, which can worsen in the presence of asynchronies. Asynchronies have been associated with worse overall prognosis, but the direct causal relation between poor patient-ventilator interaction and worse outcomes has yet to be clearly demonstrated. Critical care patients generate huge volumes of data that are vastly underexploited. New monitoring systems can analyze waveforms together with other inputs, helping us to detect, analyze, and even predict asynchronies. Big data approaches promise to help us understand asynchronies better and improve their diagnosis and management. (Continued on next page) © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 2 of 14 (Continued from previous page) Conclusions: Although our understanding of asynchronies has increased in recent years, many questions remain to be answered. Evolving concepts in asynchronies, lung crosstalk with other organs, and the difficulties of data management make more efforts necessary in this field. Keywords: Patient-ventilator interaction, Asynchronies, Mechanical ventilation, Outcome, Heart lung interaction, Psychological disorders, Cognitive, ICU, Critically ill, Big data Background Invasive mechanical ventilation is the most common means of life support applied in critical care medicine. Although mechanical ventilation often helps save lives, the mortality associated with this technique is very high. In addition, survivors of mechanical ventilation may experi- ence significant long-term morbidity resulting in substantially reduced functional status and ability to complete activities of daily living [1–3]. Optimal patient-ventilator interaction is cru- cial to assure comfort with mechanical ventilation and to avoid poor outcomes [4]. Patient-ventilator asynchronies (PVA) are the consequence of a mismatch between patients’ needs and the assistance delivered by the ventilator. PVA can be classified depending on the phase of the respiratory cycle in which they occur. The most frequent PVA are ineffective ef- forts, followed by double cycling. Its causes, consequences, and management vary depending on the type (Figs. 1 and 2) [5, 6]. This review article aims to summarize what is known about patient-ventilator interaction and asynchronies in mechanical ventilation, to show its effects on outcomes, and to describe new directions in research about these questions. Fig. 1 Representation and description of the most common asynchronies. Ineffective efforts, double cycling, reverse triggering, and inspiratory airflow dyssynchrony are graphically represented and described together with their causes. Red arrows indicate where the asynchrony described is present de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 3 of 14 Fig. 2 Inspiratory airflow dyssynchrony. Sequence of airflow and airway pressure waveforms corresponding to a same patient in the same day ventilated in assist volume control mode. Set airflow is insufficient for the patient’s needs and originated different degrees of airflow dyssynchrony or starvation. a Mild airflow dyssynchrony. b, c The progression of airflow dyssynchrony through a more severe stage. d The appearance of double cycling secondary to a huge and large inspiratory effort Main text Evolving concepts on patient-ventilator interaction and asynchronies Patient-ventilator interaction has been investigated for years [5, 7, 8]. Authors have ex- amined various factors related to ventilator mode, ventilator settings, and patient char- acteristics that can affect patient-ventilator interaction [4, 5, 9], and have identified many types of asynchronies. Some factors associated with different types of asyn- chronies have been analyzed, and different mechanisms to reduce their incidence have been studied [10]. Nevertheless, detecting PVA remains a challenge, requiring the ap- plication of advanced knowledge about respiratory physiology to interpret ventilator waveforms by analyzing their shape during different periods of the breath cycle (inspir- ation, transition from inspiration to expiration, and expiration) [5, 6, 8, 11, 12]. Until recently, such analyses required the physical presence of an expert physician at the bed- side and were thus only possible during brief, intermittent periods. PVA occurs when there is a mismatch between the ventilator and the patient in terms of demand or breath delivery timing. Recently, Pham et al. [6] proposed a classification of PVA based on the appropriateness of the level of assistance provided by the de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 4 of 14 ventilator. Assistance is deemed insufficient when the ventilator fails to meet the pa- tient’s flow demand. Inspiratory airflow dyssynchrony due to insufficient ventilator air- flow (also named flow starvation) results in the patient’s inspiratory effort continuing beyond the ventilator’s inspiratory time. When the patient’s effort is strong enough, a second breath can be triggered with no or minimal expiration (called double cycling or breath stacking), resulting in a potentially dangerous increase in tidal volume. Inspira- tory airflow dyssynchrony develops mainly when ventilators are set to deliver fixed flow and/or lower tidal volumes in patients with high inspiratory flow demands that vary from breath to breath [13, 14]. Potential consequences of low assistance are excessive load on the respiratory muscles, air hunger promoting limbic, paralimbic, and cerebel- lar activation in the brain [15], and ventilator-induced lung injury due to excessive tidal volume. Moreover, strong inspiratory efforts can increase transvascular pressure gradi- ents and tidal recruitment associated with pendelluft flow and regional lung overdisten- sion [16, 17]. Vigorous spontaneous efforts impact non-dependent and dependent lung regions differently, increasing inspiratory distension but also apparently worsening in- jury in the dependent lung because diaphragm contraction is poorly transmitted to the remainder of the pleural surface and is thus “confined” to the dependent lung [18]. It can be difficult to detect asynchronies due to insufficient assistance. By contrast, assistance is deemed excessive when the ventilator provides flow in excess of the patient’s demand. Patients with low inspiratory drive due to sedation or excessive ventilator assistance can develop ineffective efforts occurring during either in- spiration or expiration, delayed or prolonged cycling, and reverse triggering [6]. The concept of reverse triggering is evolving. Reverse triggering is a frequently under-recognized form of PVA in which the patient’s respiratory center is activated in response to a passive insufflation of the lungs. This PVA originates in respiratory muscle contractions triggered by the ventilator [19]. The physiologic mechanism re- sponsible for reverse triggering seems to be related with mechanoreceptors in the mus- cles and/or chest wall or in complex spinal reflexes [6]. Passive insufflation of the lungs activates the patient’s neurological respiratory center [20]. Recent research has found that reverse triggering could occur not only in patients with acute respiratory distress syndrome or diagnosed of brain death but in all patients receiving mechanical ventila- tion. Since reverse triggering might be more frequent than expected and could be asso- ciated with lung or diaphragm injury, the incidence and causes of reverse triggering warrant urgent investigation [6, 21, 22]. Esophageal pressure monitoring can help to identify this PVA in deeply sedated patients: a drop in esophageal pressure can be re- lated to diaphragmatic contractions triggered by ventilator insufflations [19]. Reverse triggering can result in stretching in the dependent lung. Proportional to negative intra- thoracic pressure, stretching due to reverse triggering can be equivalent to that caused by applying 15 ml/kg tidal volume. Yoshida et al. [18] recently demonstrated how re- verse triggering can worsen pre-existing lung injury through a pendelluft effect from non-dependent lung areas toward dependent areas due to poor transmission of the dia- phragm contraction across the pleural surface in an injured lung. Moreover, reverse triggering can result in increased strain and stretch due to breath stacking during double cycling caused by insufficient assistance [19, 23]. In a recent publication, we used the term double cycling to refer to both reverse-triggered or patient-triggered mechanical breaths occurring at any point in de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 5 of 14 mechanical ventilation [21]. Other authors [24] use double cycling only when the first breath in a reverse-triggering event is a ventilator-programmed breath not triggered by the patient. Only the breaths originated by a patient’s high inspiratory drive were con- sidered as double triggering. Moreover, reverse triggering that does not cause double cycling can be considered an ineffective effort during the different phases of inspiration. Several authors have speculated that reverse triggering without double cycling can cause lengthening contractions of the diaphragm and with double cycling breath-stacking with increased tidal volume in assist pressure control mode, and both tidal volume and airway pressure in assist volume control mode. Recent investigations suggest that reverse triggering is common in critical patients. Interestingly, de Haro et al. [21] found that one third of double-cycling breaths were reverse-triggered. Clinicians must differentiate between double cycling due to insufficient assistance and double cyc- ling due to reverse triggering because these phenomena call for different treatments. Double cycling due to insufficient assistance is associated with rapid respiratory rates, low ventilator airflow, and short ventilator inspiratory time [21, 25]; by contrast, double cycling due to reverse triggering is associated with deep sedation in patients not trig- gering the ventilator. However, the mechanisms involved in reverse triggering are poorly understood, so the best treatment approach remains to be determined [6]. At present, detecting these types of PVA requires trained observers analyzing waveforms on ventilator screens at the bedside. Heart-lung interaction in patients with asynchronies The heart and lungs are anatomically and functionally linked. The interactions between cardiovascular and respiratory physiology are very complex and include effects related to changes in intrathoracic pressure and lung volumes [26, 27]. Moreover, the hemodynamic effects of ventilation and asynchronies depend on the hemodynamics’ stability and the previous status of the cardiopulmonary system. In mechanically ventilated patients, the inspiratory increase in intrathoracic pressure reduces venous return by increasing right atrial pressure and reduces left ventricular afterload by decreasing transmural left ventricular systolic pressure. Conversely, it can also increase the afterload of the right ventricle considerably. Increased right ventricu- lar afterload results from progressive increases in transpulmonary pressure (difference between alveolar pressure and pleural pressure) associated with increasing lung volume; this effect can be especially important in patients with acute respiratory distress syn- drome. Moreover, left ventricular preload can be affected by changes in right ventricu- lar preload and by ventricular interdependence [26–28]. Interestingly, heart-lung interactions may be useful to assess fluid responsiveness in critical care [28, 29]. urthermore, changes in heart load conditions can in turn lead to lung injury. In a re- cent experimental study, Katira et al. [30] showed that abrupt deflation after sustained inflation can cause acute lung injury; in critical patients, deflation could occur when positive end-expiratory pressure is removed or the patient is disconnected from the ventilator. Apparently, lung injury results from acute left ventricular decompensation (increased left ventricular preload and afterload), which raises the pressure in the pul- monary microvasculature, injuring the endothelium and causing edema, which is in turn potentiated by the surge in pulmonary perfusion. Whether this phenomenon de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 6 of 14 observed in experimental animals could occur in patients under mechanical ventilation warrants further investigation. Unfortunately, the hemodynamic effects caused by different PVA have not been ex- tensively studied. In theory, ineffective efforts decrease intrathoracic pressure and could consequently increase venous return and right ventricular filling. However, there are no physiological data to confirm this hypothesis. On the other hand, our group recently showed that the tidal volume accumulated during double cycling is very high, some- times even doubling that of normal breaths in volume-targeted modes [21]. In addition, the peak pressure of the second breath is generally greater than that of the first. Both increased volume and pressure could significantly affect preload and afterload, but the hemodynamic consequences of these effects have not been evaluated. Although dynamic parameters based on heart-lung interactions such as pulse pres- sure variation (PPV) and stroke volume variation (SVV) accurately predict fluid respon- siveness in patients passively adapted to the ventilator, these parameters are not good predictors of fluid responsiveness in patients with spontaneous respiratory activity probably due to multiple causes such as increased preload induced by negative intra- thoracic pressure during patient inspiration and the variability of the breathing pattern [31]. In the presence of asynchronies, this effect could be magnified. In a recent study examining whether PVA affected PPV’s ability to predict fluid re- sponsiveness in patients receiving pressure support ventilation, Messina et al. [32] com- pared 27 patients without PVA versus 27 with PVA as determined by visual inspection of ventilator waveforms. The area under the receiver operating characteristic curve was 0.86 (CI 0.68–0.96) in patients without PVA but only 0.53 (CI 0.33–0.73) in those with PVA (p = 0.018); PPV ≥ 13% predicted fluid responsiveness with 78% sensitivity and 89% specificity in patients without PVA but only 36% sensitivity and 46% specificity in those with asynchronies. PVA significantly affected PPV prediction of fluid responsive- ness (OR 8.8 [2.0–38.0]; p = 0.003). They hypothesize that PVA affect the cyclical changes in intrathoracic pressure, resulting in unpredictable and persistent variations of right ventricular preload and left ventricular stroke volume, thereby altering the reli- ability of PPV in assessing fluid responsiveness. Nevertheless, more physiological and clinical data are needed to determine the implications of these findings in clinical practice. Can asynchronies impact major outcomes? PVA are frequent but underdiagnosed, and they have been associated with worse prog- nosis: discomfort; sleep disorders [33], which increase the need for sedatives [34]; pro- longation of mechanical ventilation [7, 35]; increased intensive care unit (ICU) and hospital stays [33]; and increased mortality [4]. Thus, it seems crucial to take action to reduce their incidence [5]. Nevertheless, a direct causal relation between poor patient-ventilator interaction and worse outcomes has yet to be clearly demonstrated, and there is no direct evidence to demonstrate that reducing PVA guarantees better outcomes. To clarify whether PVA are a direct causative factor of worse outcomes, it is neces- sary to identify and quantify the occurrence of PVA throughout the entire period of mechanical ventilation. To this end, monitoring systems have recently been developed de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 7 of 14 to enable such analyses, and these systems are helping elucidate the potential harmful physiological effects of different types of PVA [36, 37]. Monitoring systems have made possible to analyze the magnitude of PVA and how they are distributed over time, which are crucial factors in the evaluation of the impact of PVA on clinical outcomes. In a secondary analysis, Blanch et al. [4] found that al- though patients with an asynchrony index > 10% had similar rates of reintubation and tracheostomy compared to those with lower rates, an asynchrony index > 10% was as- sociated with higher ICU and hospital mortality and with a trend toward longer dur- ation of mechanical ventilation. Beyond the frequency of PVA, Vaporidi et al. [38] focused on the presence of clusters of ineffective efforts as well as their power and dur- ation, finding that all these aspects were associated with prolonged mechanical ventila- tion and higher hospital mortality and highlighting the need to examine different dimensions of patient-ventilator interaction. Finally, Rue et al. [39] used Bayesian joint modeling of bivariate and competing risks data to investigate the added value of adding information about the rate of PVA to Sequential Organ Failure Assessment (SOFA) scores to predict outcomes. They found an association between the asynchrony index and live discharge, but including this information did not improve the accuracy of the prognosis of the SOFA score alone. They concluded that a more detailed analysis of PVA, together with other multidimensional data, would be necessary to confirm a causal role on ventilated patients’ outcomes and comorbidities. It also remains to be demonstrated whether strategies to optimize patient-ventilator interactions improve outcomes. De Haro et al. [21] analyzed the incidence, mechanisms, and physiologic implica- tions of double cycling in 67 adults continuously monitored while undergoing vari- ous modes of volume- and/or pressure-targeted mechanical ventilation for more than 24 h. They found that, as previously observed by others, the volume of stacked breaths resulting from inspiratory airflow dyssynchrony can double the set tidal volume in volume-controlled ventilation [21]. This higher-than-expected tidal volume exceeds the optimal value set for protective ventilation and could harm lung tissue and respiratory muscles [21, 25], thus contributing to ventilation-associated lung injury [21, 24, 25, 40, 41]. Regarding neuropsychological outcomes, new research is exploring how mechan- ical ventilation is linked to psychological disorders observed in critically ill patients [42, 43]. Anxiety is one of the most common psychological symptoms reported by critically ill patients [44], affecting between 30 and 80% of all patients [45]. Pa- tients on mechanical ventilation report worries about breathlessness, choking, or being left alone [46], and up to 47% of ICU survivors report having felt anxiety and/or fear during mechanical ventilation [47]. It seems that, even after tracheot- omy, levels of anxiety do not decrease [44]. However, the direct link between anx- iety and asynchronies in mechanically ventilated patients has not been explored yet. Nevertheless, respiratory difficulties, including synchronizing with the respir- ator, cough, and dyspnea [45, 46], are considered potent drivers of anxiety, agony, and insecurity. Anxiety has been independently associated with dyspnea in critically ill patients undergoing mechanical ventilation, and when ventilator settings are ad- justed, dyspnea is reduced in at least a third of patients [48]. Therefore, asyn- chronies and anxiety in ICU patients could be, somehow, potentially related. de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 8 of 14 Anxiety is a state of psychological distress and physiological discomfort that, if prolonged, delays healing and predisposes to difficulties in weaning from mechan- ical ventilation [44]. Jubran et al. [49] also found that mechanically ventilated pa- tients with depressive symptoms were three times more likely to experience weaning failure and death. Furthermore, high levels of anxiety often prompt profes- sionals to apply higher sedation doses or restraints, leading to immobility, de- creased level of consciousness, and loss of protective reflexes [46]. Despite the importance of the early detection of adverse psychological outcomes dur- ing ICU stay, neither anxiety nor depressive symptoms are routinely assessed in mech- anically ventilated critically ill patients. In fact, most of the little information available about psychological disorders derives from the studies in ICU survivors [46]. After ICU discharge, 23 to 50% of survivors have generalized, nonspecific anxiety [2, 50, 51], and although it improves over time, anxiety levels in ICU survivors are higher than those observed in medical inpatients (5 to 20%) [2]. Nevertheless, 15 to 43% of survivors con- tinue to have symptoms of anxiety 6 months [51] and 1 year [52] after discharge, and 60% also have other mental health problems such as post-traumatic stress disorder (PTSD) [53–55] and depression [50, 56]. These long-term mental health problems in ICU survivors are often associated with worse quality of life [2, 3]. Big data techniques applied to large observational databases to improve the management of ventilated patients In medical research, pragmatic research attempts to approach problems from a broad and, in a sense, a realistic perspective. For example, observational studies of medical in- terventions may more closely reflect daily clinical practice [57]. However, the main drawback of observational studies is the potential bias and confounding factors, being difficult to establish an independent association between methods/strategies/treatments and outcome variables. The access to large databases of heterogeneous populations with high levels of complexity is key for observational studies to the extent researchers are aware of confounding and able to measure them. Mechanically ventilated critically ill patients continuously generate huge volumes of data of varying complexity and temporal resolution [36, 58]. Some data (e.g., physio- logic waveforms) are generated at very high temporal resolutions, while others are gen- erated at much lower temporal resolutions. Whereas data about laboratory test results might be generated on a daily basis, two medical devices (e.g., multiparameter monitor and ventilator) connected to a mechanically ventilated patient record about 10 different waveforms (electrocardiographic, plethysmographic, capnographic, respiratory, arterial blood pressure, airway pressure, gas flow, volume) at 200 points per second or more, thus producing a total of 172.8 million data points each day or 1.04 billion over the average duration of mechanical ventilation. Traditionally, most of these data are under- exploited, becoming unavailable immediately or within 24 to 48 h [58, 59]. Thus, the potential to discover new patterns and extract valuable information to support diagno- sis or to predict the time course of a patient’s condition is lost. During mechanical ventilation, patient-ventilator interaction alternates between pe- riods of complete synchrony and periods with clusters of frequent asynchronies [38]. Yet, physicians optimize mechanical ventilation by assessing waveforms on bedside de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 9 of 14 monitors based on their understanding of the physiological principles involved and evi- dence from previous studies; however, today’s guidelines for ICUs derive from a scant evidence base, considering the potential evidence base given the massive data generated in the ICU [59]. It should come as no surprise that most physicians perform poorly at managing patient-ventilator interactions and do not recognize common forms of patient-ventilator asynchronies [11], but an equally important problem is that even the most highly skilled professionals can observe only a small proportion of these wave- forms, thus increasing the probability of misinterpretation due to sampling errors. For this reason, there is an urgent need for technological and analytic tools to deal with these pragmatic observational data. Big data promises to help refine our approach to PVA, improving our understanding of the various phenomena, their detection, and their treatment. At present, the continuous and automatic detection of asynchronies is an emerging technological area. Table 1 shows a comparison of some automated methods for patient-ventilator asynchrony detection [60]. However, it can be challen- ging to implement big data solutions in ICUs. These solutions involve new ethical is- sues; require investments in technical deployment to resolve problems related to interoperability, network connections, digital storage, etc.; depend on active Table 1 Comparison of some automated methods for patient-ventilator asynchrony detection Type of PVA Algorithm Performance Gholami Cycling asynchrony (premature ML: Random forest and k-fold cross Se 89–97%, Sp 93– et al. (2018) and delayed cycling) validation 99%, Kappa index 0.9 [69] Pressure and airflow signals N = 11 patients (1377 breaths) ventMAP Double-trigger and breath Rule-based algorithm Se 94–96.7%, Sp 92– platform stacking Pressure and airflow signals 98%, Acc 92.2–97.7% Adams Derivation cohort, N = 16 patients (on the validation et al. (5075 breaths); validation cohort, cohort) (2017) [70] N = 17 patients (4644 breaths) NeuroSync Patient-ventilator interaction Rule-based timings algorithm ICC 0.95 vs. Colombo index classification (asynchronous, EAdi and pressure signals et al. (2011) [5] Sinderby et dyssynchronous or synchronous) N = 24 patients al. (2013) [71] Better Ineffective efforts during Rule-based combining digital signal Se 91.5%, Sp 91.7%, Care® expiration processing techniques and ROC PPV 80.3%, NPV 96.7%, system curves Kappa index 0.797 Blanch et Airflow signal (vs. the expert’s al. (2012) Cohort 1: N = 8 patients (1024 classification) [37] breaths) Se 65.2%, Sp 99.3%, Cohort 2: N = 8 patients (9600 PPV 90.8%, NPV 96.5%, breaths) with EAdi signal as Kappa index 0.739 reference (vs. EAdi signal) Gutierrez et Index for asynchronous/no Time-frequency analysis Se 83%, Sp 83% when al. (2011) asynchronous breaths Airflow signals index < 43% for AI > [72] N = 110 patients 10% Mulqueeny Ineffective triggering and double Rule-based and digital signal Se 91%, Sp 97% et al. (2007) triggering processing methods [73] Airflow and pressure signals N = 20 patients (3343 breaths) PVI monitor Ineffective efforts Rule-based Se 79.7% Younes et Equation of motion from pressure, al. (2007) airflow, and Peso signals [74] N = 21 patients Abbreviations: ML machine learning, Se sensitivity, Sp specificity, ICC intraclass correlation coefficient, Acc overall accuracy, Peso esophageal pressure, PPV positive predictive value, NPV negative predictive value, ROC receiver operating characteristics, AI asynchrony index according to the definition from Thille et al. [7] de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 10 of 14 collaboration among experts from a wide range of areas (physicians, biologists, statisti- cians, and engineers); and must meet quality standards [61]. Big data solutions to sup- port daily clinical decision making and improve patient care are based on storing and exploring extremely large observational datasets [58, 61–63]. Fortunately, some steps are being taken in this direction. The Multiparameter and In- telligent Monitoring in Intensive Care (MIMIC) database contains thousands of ICU records reflecting daily clinical routines from a wide variety of sources, making it ex- tremely useful for assessing clinical decision, monitoring algorithms, and testing new research hypothesis [64]. Another interesting initiative is the AEGLE project [65, 66], aimed at identifying ineffective efforts with big data analytics. AEGLE also addresses lung overstretching during assisted ventilation, identifying injurious high levels of pres- sure, and predicting the risk of this phenomenon developing within the next few mi- nutes. A recent proof-of-concept study showed that it is feasible to use Hidden Markov Models to predict PVA in critically ill patients and to infer the probability that the number of asynchrony events will be above a given threshold [67]. All these approaches have potential health and economic benefits. Given the growing interest in devising better evidence-based care in the ICU, physicians should become familiar with the op- portunities and challenges of big data [68] (Fig. 3). Fig. 3 Future medical trends in real-time clinical decision making for mechanically ventilated critically patients in ICU. With adequate interoperability and data storage, clinical decision support systems based on big data analytics can automatically recognize patterns in data; moreover, these systems have the ability to improve continuously by “learning” from past and new inputs. Using the cloud for big data analytics makes it easier to make predictions and better understand trends de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 11 of 14 Conclusion The results of observational studies evidence that poor patient-ventilator interaction might cause lung and vascular injury and thereby increase mortality. The effects of asynchronies on clinical outcomes remain to be clarified, but the type and presentation of asynchronies over time seems important. Together with damage resulting from the patient’s original disease, the short- and long-term consequences of poor patient-ventilator interaction can have devastating effects that hinder discharged pa- tients’ complete return to normal activities. Therefore, critical care professionals must strive to improve patient-ventilator interaction. Observational studies could have some limitations on establishing association between patient-ventilator asynchronies and out- comes, and future multicenter studies with bigger population are needed. Finally, soft- ware solutions that can identify and analyze asynchronies online and offline may lead to better care and improve outcomes. Abbreviations Acc: Overall accuracy; AI: Asynchrony index; CI: Confidence interval; EAdi: Electric activity diaphragm; ICC: Intraclass correlation coefficient; ICU: Intensive care unit; ML: Machine learning; NPV: Negative predictive value; OR: Odds ratio; PAW: Pressure airway; PPV: Positive predictive value; PuPV: Pulse pressure variation; PTSD: Post-traumatic stress disorder; PVA: Patient-ventilator asynchronies; ROC: Receiver operating characteristics; Se: Sensibility; SOFA: Sequential Organ Failure Assessment; Sp: Specificity; SVV: Stroke volume variation; Vt: Tidal volume Acknowledgements The authors thank Mr. John Giba for the invaluable support in editing the manuscript and the collaboration of the Asynchronies in the Intensive Care Unit (ASYNICU) Group: Candelaria de Haro, Josefina López-Aguilar, Rudys Magrans, Sol Fernández-Gonzalo, Gemma Gomà, Encarna Chacón, Ana Ochagavia, Lluís Blanch (Critical Care Center, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona. Sabadell, Spain); Jaume Montanya, Bernat Sales (Better Care. Barcelona, Spain); Enrico Lena, Umberto Lucangelo (Department of Perioperative Medicine, Intensive Care and Emergency, Cattinara Hospital, Trieste University. Trieste, Italy); Rafael Fernández, Carles Subirà (ICU, Fundació Althaia, Universitat Internacional de Catalunya. Manresa, Spain); Guillermo M Albaiceta (Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Oviedo, and Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo. Oviedo, and CIBERES, Instituto de Salud Carlos III, Madrid, Spain); Gastón Murias (Critical Care Department, Hospital Británico. Buenos Aires, Argentina); Robert M Kacmarek (Department of Respiratory Care, Department of Anesthesiology, Massachusetts General Hospital, Harvard Medical School. Boston, MA, USA). Funding This work was funded by projects PI13/02204 and PI16/01606, integrated in the Plan Nacional de R+D+I and co-funded by the ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER). CIBER Enfermedades Respiratorias, and Fundació Parc Taulí. This article did not receive sponsorship for publication. Availability of data and materials Not applicable. About this supplement This article has been published as part of the supplement Intensive Care Medicine Experimental Volume 7 Supplement 1 2019: Proceedings from the Third International Symposium on Acute Pulmonary Injury and Translational Research (INSPIRES III). The full contents of the supplement are available at https://icm-experimental.springeropen.com/articles/ supplements/volume-7-supplement-1. Authors’ contributions CdH and LB have contributed to the section “Evolving concepts on patient-ventilator interaction and asynchronies”. AO has contributed to the section “Heart Lung Interaction in patients with asynchronies”. JLA, SFG, and GNV have con- tributed to the section “Can asynchronies impact major outcomes?” RM and JM have contributed to the section “Big data techniques applied to large observational databases to improve the management of ventilated patients”. All au- thors read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. de Haro et al. Intensive Care Medicine Experimental 2019, 7(Suppl 1):43 Page 12 of 14 Competing interests Mr. Montanya and Dr. Blanch own stock options of Better Care SL, which is a research and development spinoff of Corporació Sanitària Parc Taulí (Spain). Drs. Blanch discloses that he is inventor of one Corporació Sanitaria Parc Taulí owned US patent: “Method and system for managed related patient parameters provided by a monitoring device,” U.S. Patent No. 12/538,940. The remaining authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1 Critical Care Center, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí 1, 08208 Sabadell, Spain. 2CIBERES, Instituto de Salud Carlos III, Madrid, Spain. 3 CIBERSAM, Instituto de Salud Carlos III, Madrid, Spain. 4Better Care, Barcelona, Spain. Received: 6 February 2019 Accepted: 7 March 2019 Published: 25 July 2019 References 1. Mehta AB, Syeda SN, Wiener RS, Walkey AJ (2015) Epidemiological trends in invasive mechanical ventilation in the United States: a population-based study. J Crit Care 30:1217–1221 2. Jackson JC, Mitchell N, Hopkins RO (2015) Cognitive functioning, mental health, and quality of life in ICU survivors: an overview. Psychiatr Clin North Am 38:91–104 3. 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