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Abstract Background Popularity of electrical impedance tomography (EIT) and esophageal pressure (Pes) monitoring in the ICU is increasing, but there is uncertainty regarding their bedside use within a personalized ventilation strategy. We aimed to gather insights about the current experiences and perceived role of these physiological monitoring techniques, and to identify barriers and facilitators/solutions for EIT and Pes implementation. Methods Qualitative study involving (1) a survey targeted at ICU clinicians with interest in advanced respiratory monitoring and (2) an expert focus group discussion. The survey was shared via international networks and personal communication. An in-person discussion session on barriers, facilitators/solutions for EIT implementation was organized with an international panel of EIT experts as part of a multi-day EIT meeting. Pes was not discussed in-person, but we found the focus group results relevant to Pes as well. This was confirmed by the survey results and four additional Pes experts that were consulted. Results We received 138 survey responses, and 26 experts participated in the in-person discussion. Survey participants had diverse background [physicians (54%), respiratory therapists (19%), clinical researchers (15%), and nurses (6%)] with mostly > 10 year ICU experience. 84% of Pes users and 74% of EIT users rated themselves as competent to expert users. Techniques are currently primarily used during controlled ventilation for individualization of PEEP (EIT and Pes), and for monitoring lung mechanics and lung stress (Pes). EIT and Pes are considered relevant techniques to guide ventilation management and is helpful for educating clinicians; however, 57% of EIT users and 37% of Pes users agreed that further validation is needed. Lack of equipment/materials, evidence-based guidelines, clinical protocols, and/or the time-consuming nature of the measurements are main reasons hampering Pes and EIT application. Identified facilitators/solutions to improve implementation include international guidelines and collaborations between clinicians/researcher and manufacturers, structured courses for training and use, easy and user-friendly devices and standardized analysis pipelines. Conclusions This study revealed insights on the role and implementation of advanced respiratory monitoring with EIT and Pes. The identified barriers, facilitators and strategies can serve as input for further discussions to promote the development of EIT-guided or Pes-guided personalized ventilation strategies.

Abstract Background Electrical Impedance Tomography (EIT) can quantify ventilation in the two lungs and be used to measure the airway opening pressure (AOP) of each lung. Asymmetrical AOPs can cause inter-lung insufflation delay. Objectives To assess the relation between AOP asymmetry and inter-lung insufflation delay at different PEEP levels. Methods Patients with acute hypoxemic respiratory failure and airway closure were included. Low-flow pressure-volume curves and EIT signal were recorded during controlled ventilation and for some patients in pressure support ventilation. Results 23 patients were studied, 22 patients had ARDS, 9 patients had asymmetrical airway closure with an AOP of 10 [6–13] cmH20 in the sicker lung (AOPsicker) vs. 5 [3–9, ] cmH20 in the healthier lung. During a low flow inflation, the inter-lung inflation delay was 0 [0-112]ms vs. 1450 [375–2400]ms in patients without or with asymmetrical AOPs, p

Abstract Background Sigh breaths may impact outcomes in acute hypoxemic respiratory failure (AHRF) during assisted mechanical ventilation. We investigated whether sigh breaths may impact mortality in predefined subgroups of patients enrolled in the PROTECTION multicenter clinical trial according to: 1.the physiological response in oxygenation to Sigh (responders versus non-responders) and 2.the set levels of positive end-expiratory pressure (PEEP) (High vs. Low-PEEP). If mortality differed between Sigh and No Sigh, we explored physiological daily differences at 7-days. Results Patients were randomized to pressure support ventilation (PSV) with Sigh (Sigh group) versus PSV with no sigh (No Sigh group). (1) Sighs were not associated with differences in 28-day mortality in responders to baseline sigh-test. Contrarily-in non-responders-56 patients were randomized to Sigh (55%) and 28-day mortality was lower with sighs (17%vs.36%, log-rank p = 0.031). (2) In patients with PEEP > 8cmH2O no difference in mortality was observed with sighs. With Low-PEEP, 54 patients were randomized to Sigh (48%). Mortality at 28-day was reduced in patients randomised to sighs (13%vs.31%, log-rank p = 0.021). These findings were robust to multivariable adjustments. Tidal volume, respiratory rate and ventilatory ratio decreased with Sigh as compared with No Sigh at 7-days. Ventilatory ratio was associated with mortality and successful extubation in both non-responders and Low-PEEP. Conclusions Addition of Sigh to PSV could reduce mortality in AHRF non-responder to Sigh and exposed to Low-PEEP. Results in non-responders were not expected. Findings in the low PEEP group may indicate that insufficient PEEP was used or that Low PEEP may be used with Sigh. Sigh may reduce mortality by decreasing physiologic dead space and ventilation intensity and/or optimizing ventilation/perfusion mismatch. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT03201263.

Abstract Side effects of mechanical ventilation, such as ventilator-induced diaphragmatic dysfunction (VIDD) and ventilator-induced lung injury (VILI), occur frequently in critically ill patients. Phrenic nerve stimulation (PNS) has been a valuable tool for diagnosing VIDD by assessing respiratory muscle strength in response to magnetic PNS. The detection of pathophysiologically reduced respiratory muscle strength is correlated with weaning failure, longer mechanical ventilation time, and mortality. Non-invasive electromagnetic PNS designed for diagnostic use is a reference technique that allows clinicians to measure transdiaphragm pressure as a surrogate parameter for diaphragm strength and functionality. This helps to identify diaphragm-related issues that may impact weaning readiness and respiratory support requirements, although lack of lung volume measurement poses a challenge to interpretation. In recent years, therapeutic PNS has been demonstrated as feasible and safe in lung-healthy and critically ill patients. Effects on critically ill patients’ VIDD or diaphragm atrophy outcomes are the subject of ongoing research. The currently investigated application forms are diverse and vary from invasive to non-invasive and from electrical to (electro)magnetic PNS, with most data available for electrical stimulation. Increased inspiratory muscle strength and improved diaphragm activity (e.g., excursion, thickening fraction, and thickness) indicate the potential of the technique for beneficial effects on clinical outcomes as it has been successfully used in spinal cord injured patients. Concerning the potential for electrophrenic respiration, the data obtained with non-invasive electromagnetic PNS suggest that the induced diaphragmatic contractions result in airway pressure swings and tidal volumes remaining within the thresholds of lung-protective mechanical ventilation. PNS holds significant promise as a therapeutic intervention in the critical care setting, with potential applications for ameliorating VIDD and the ability for diaphragm training in a safe lung-protective spectrum, thereby possibly reducing the risk of VILI indirectly. Outcomes of such diaphragm training have not been sufficiently explored to date but offer the perspective for enhanced patient care and reducing weaning failure. Future research might focus on using PNS in combination with invasive and non-invasive assisted ventilation with automatic synchronisation and the modulation of PNS with spontaneous breathing efforts. Explorative approaches may investigate the feasibility of long-term electrophrenic ventilation as an alternative to positive pressure-based ventilation.

Abstract Background Extubation failure is associated with increased mortality. Cough ineffectiveness may be associated with extubation failure, but its quantification for patients undergoing weaning from invasive mechanical ventilation (IMV) remains challenging. Methods Patients under IMV for more than 24 h completing a successful spontaneous T-tube breathing trial (SBT) were included. At the end of the SBT, we performed quantitative sonometric assessment of three successive coughing efforts using a sonometer. The mean of the 3-cough volume in decibels was named Sonoscore. Results During a 1-year period, 106 patients were included. Median age was 65 [51–75] years, mainly men (60%). Main reasons for IMV were acute respiratory failure (43%), coma (25%) and shock (17%). Median duration of IMV at enrollment was 4 [3–7] days. Extubation failure occurred in 15 (14%) patients. Baseline characteristics were similar between success and failure extubation groups, except percentage of simple weaning which was lower and MV duration which was longer in extubation failure patients. Sonoscore was significantly lower in patients who failed extubation (58 [52–64] vs. 75 [70–78] dB, P

Abstract Acute respiratory distress syndrome (ARDS) has a ~ 40% mortality rate with an increasing prevalence exacerbated by the COVID-19 pandemic. Mechanical ventilation is the primary means for life-saving support to buy time for lung healing in ARDS patients, however, it can also lead to ventilator-induced lung injury (VILI). Effective strategies to reduce or prevent VILI are necessary but are not currently delivered. Therefore, we aim at evaluating the current imaging technologies to visualize where pressure and volume being delivered to the lung during mechanical ventilation; and combining plasma biomarkers to guide management of mechanical ventilation. We searched PubMed and Medline using keywords and analyzed the literature, including both animal models and human studies, to examine the independent use of computed tomography (CT) to evaluate lung mechanics, electrical impedance tomography (EIT) to guide ventilation, ultrasound to monitor lung injury, and plasma biomarkers to indicate status of lung pathophysiology. This investigation has led to our proposal of the combination of imaging and biomarkers to precisely deliver mechanical ventilation to improve patient outcomes in ARDS.

Abstract Background Several noninvasive ventilatory supports rely in their design on high oxygen consumption which may precipitate oxygen shortage, as experienced during the COVID-19 pandemic. In this bench-to-bedside study, we assessed the performance of a new continuous positive airway pressure (CPAP) device integrating a large reservoir (“Bag-CPAP”) designed to minimize oxygen consumption, and compared it with other CPAP devices. Methods First, a bench study compared the performances of Bag-CPAP and four CPAP devices with an intensive care unit ventilator. Two FiO2 targets (40–60% and 80–100%) at a predefined positive end expiratory pressure (PEEP) level between 5 and 10 cm H2O were tested and fraction of inspired oxygen (FiO2) and oxygen consumption were measured. Device-imposed work of breathing (WOB) was also evaluated. Second, an observational clinical study evaluated the new CPAP in 20 adult patients with acute respiratory failure in two hospitals in France. Actual FiO2, PEEP, peripheral oxygen saturation, respiratory rate, and dyspnea score were assessed. Results All six systems tested in the bench study reached the minimal FiO2 target of 40% and four reached at least 80% FiO2 while maintaining PEEP in the predefined range. Device-delivered FiO2/consumed oxygen ratio was the highest with the new reservoir-based CPAP irrespective of FiO2 target. WOB induced by the device was higher with Bag-CPAP. In the clinical study, Bag-CPAP was well tolerated and could reach high (> 90%) and moderate (> 50%) FiO2 with an oxygen flow rate of 15 [15–16] and 8 [7–9] L/min, respectively. Dyspnea score improved significantly after introduction of Bag-CPAP, and SpO2 increased. Conclusions In vitro, Bag-CPAP exhibited the highest oxygen saving properties albeit had increased WOB. It was well accepted clinically and reduced dyspnea. Bag-CPAP may be useful to treat patients with acute respiratory failure in the field, especially when facing constraints in oxygen delivery.

Abstract Background In ARDS, the PEEP level associated with the best respiratory system compliance is often selected; however, intra-tidal recruitment can increase compliance, falsely suggesting improvement in baseline mechanics. Tidal lung hysteresis increases with intra-tidal recruitment and can help interpreting changes in compliance. This study aims to assess tidal recruitment in ARDS patients and to test a combined approach, based on tidal hysteresis and compliance, to interpret decremental PEEP trials. Methods A decremental PEEP trial was performed in 38 COVID-19 moderate to severe ARDS patients. At each step, we performed a low-flow inflation-deflation manoeuvre between PEEP and a constant plateau pressure, to measure tidal hysteresis and compliance. Results According to changes of tidal hysteresis, three typical patterns were observed: 10 (26%) patients showed consistently high tidal-recruitment, 12 (32%) consistently low tidal-recruitment and 16 (42%) displayed a biphasic pattern moving from low to high tidal-recruitment below a certain PEEP. Compliance increased after 82% of PEEP step decreases and this was associated to a large increase of tidal hysteresis in 44% of cases. Agreement between best compliance and combined approaches was accordingly poor (K = 0.024). The combined approach suggested to increase PEEP in high tidal-recruiters, mainly to keep PEEP constant in biphasic pattern and to decrease PEEP in low tidal-recruiters. PEEP based on the combined approach was associated with lower tidal hysteresis (92.7 ± 20.9 vs. 204.7 ± 110.0 mL; p

BackgroundAirway closure, which refers to the complete collapse of the airway, has been described under mechanical ventilation during anesthesia and more recently in adult patients with acute respiratory distress syndrome (ARDS). A ventilator maneuver can be used to identify airway closure and measure the pressure required for the airway to reopen, known as the airway opening pressure (AOP). Without that maneuver, AOP is unknown to clinicians.ObjectiveThis study aims to demonstrate the technical adaptation of the adult maneuver for children and illustrate its application in two cases of pediatric ARDS (p-ARDS).MethodsA bench study was performed to adapt the maneuver for 3–50 kg patients. Four maneuvers were performed for each simulated patient, with 1, 2, 3, and 4 s of insufflation time to deliver a tidal volume (Vt) of 6 ml/kg by a continuous flow.ResultsAirway closure was simulated, and AOP was visible at 15 cmH2O with a clear inflection point, except for the 3 kg simulated patient. Regarding insufflation time, a 4 s maneuver exhibited a better performance in 30 and 50 kg simulated patients since shorter insufflation times had excessive flowrates (>10 L/min). Below 20 kg, the difference in resistive pressure between a 3 s and a 4 sec maneuver was negligible; therefore, prolonging the maneuver beyond 3 s was not useful. Airway closure was identified in two p-ARDS patients, with the pediatric maneuver being employed in the 28 kg patient.ConclusionsWe propose a pediatric AOP maneuver delivering 6 ml/kg of Vt at a continuous low-flow inflation for 3 s for patients weighing up to 20 kg and for 4 s for patients weighing beyond 20 kg.

Abstract Background Mechanical ventilation has side effects such as ventilator-induced diaphragm dysfunction, resulting in prolonged intensive care unit length of stays. Artificially evoked diaphragmatic muscle contraction may potentially maintain diaphragmatic muscle function and thereby ameliorate or counteract ventilator-induced diaphragm dysfunction. We hypothesized that bilateral non-invasive electromagnetic phrenic nerve stimulation (NEPNS) results in adequate diaphragm contractions and consecutively in effective tidal volumes. Results This single-centre proof-of-concept study was performed in five patients who were 30 [IQR 21–33] years old, 60% (n = 3) females and undergoing elective surgery with general anaesthesia. Following anaesthesia and reversal of muscle relaxation, patients received bilateral NEPNS with different magnetic field intensities (10%, 20%, 30%, 40%); the stimulation was performed bilaterally with dual coils (connected to one standard clinical magnetic stimulator), specifically designed for bilateral non-invasive electromagnetic nerve stimulation. The stimulator with a maximal output of 2400 Volt, 160 Joule, pulse length 160 µs at 100% intensity was limited to 50% intensity, i.e. each single coil had a maximal output of 0.55 Tesla and 1200 Volt. There was a linear relationship between dosage (magnetic field intensity) and effect (tidal volume, primary endpoint, p

Abstract Background There is very limited evidence identifying factors that increase respiratory drive in hypoxemic intubated patients. Most physiological determinants of respiratory drive cannot be directly assessed at the bedside (e.g., neural inputs from chemo- or mechano-receptors), but clinical risk factors commonly measured in intubated patients could be correlated with increased drive. We aimed to identify clinical risk factors independently associated with increased respiratory drive in intubated hypoxemic patients. Methods We analyzed the physiological dataset from a multicenter trial on intubated hypoxemic patients on pressure support (PS). Patients with simultaneous assessment of the inspiratory drop in airway pressure at 0.1-s during an occlusion (P 0.1) and risk factors for increased respiratory drive on day 1 were included. We evaluated the independent correlation of the following clinical risk factors for increased drive with P 0.1: severity of lung injury (unilateral vs. bilateral pulmonary infiltrates, PaO2/FiO2, ventilatory ratio); arterial blood gases (PaO2, PaCO2 and pHa); sedation (RASS score and drug type); SOFA score; arterial lactate; ventilation settings (PEEP, level of PS, addition of sigh breaths). Results Two-hundred seventeen patients were included. Clinical risk factors independently correlated with higher P 0.1 were bilateral infiltrates (increase ratio [IR] 1.233, 95%CI 1.047–1.451, p = 0.012); lower PaO2/FiO2 (IR 0.998, 95%CI 0.997–0.999, p = 0.004); higher ventilatory ratio (IR 1.538, 95%CI 1.267–1.867, p

Abstract Prone positioning is an evidence-based treatment for patients with moderate-to-severe acute respiratory distress syndrome. Lung recruitment has been proposed as one of the mechanisms by which prone positioning reduces mortality in this group of patients. Recruitment-to-inflation ratio (R/I) is a method to measure potential for lung recruitment induced by a change in positive end-expiratory pressure (PEEP) on the ventilator. The association between R/I and potential for lung recruitment in supine and prone position has not been studied with computed tomography (CT) scan imaging. In this secondary analysis, we sought to investigate the correlation between R/I measured in supine and prone position with CT and the potential for lung recruitment as measured by CT scan. Among 23 patients, the median R/I did not significantly change from supine (1.9 IQR 1.6–2.6) to prone position (1.7 IQR 1.3–2.8) (paired t test p = 0.051) but the individual changes correlated with the different response to PEEP. In supine and in prone position, R/I significantly correlated with the proportion of lung tissue recruitment induced by the change of PEEP. Lung tissue recruitment induced by a change of PEEP from 5 to 15 cmH2O was 16% (IQR 11–24%) in supine and 14.3% (IQR 8.4–22.6%) in prone position, as measured by CT scan analysis (paired t test p = 0.56). In this analysis, PEEP-induced recruitability as measured by R/I correlated with PEEP-induced lung recruitment as measured by CT scan, and could help to readjust PEEP in prone position.

Abstract Background Proportional assist ventilation with load-adjustable gain factors (PAV+) is a mechanical ventilation mode that delivers assistance to breathe in proportion to the patient’s effort. The proportional assistance, called the gain, can be adjusted by the clinician to maintain the patient’s respiratory effort or workload within a normal range. Short-term and physiological benefits of this mode compared to pressure support ventilation (PSV) include better patient-ventilator synchrony and a more physiological response to changes in ventilatory demand. Methods The objective of this multi-centre randomized controlled trial (RCT) is to determine if, for patients with acute respiratory failure, ventilation with PAV+ will result in a shorter time to successful extubation than with PSV. This multi-centre open-label clinical trial plans to involve approximately 20 sites in several continents. Once eligibility is determined, patients must tolerate a short-term PSV trial and either (1) not meet general weaning criteria or (2) fail a 2-min Zero Continuous Positive Airway Pressure (CPAP) Trial using the rapid shallow breathing index, or (3) fail a spontaneous breathing trial (SBT), in this sequence. Then, participants in this study will be randomized to either PSV or PAV+ in a 1:1 ratio. PAV+ will be set according to a target of muscular pressure. The weaning process will be identical in the two arms. Time to liberation will be the primary outcome; ventilator-free days and other outcomes will be measured. Discussion Meta-analyses comparing PAV+ to PSV suggest PAV+ may benefit patients and decrease healthcare costs but no powered study to date has targeted the difficult to wean patient population most likely to benefit from the intervention, or used consistent timing for the implementation of PAV+. Our enrolment strategy, primary outcome measure, and liberation approaches may be useful for studying mechanical ventilation and weaning and can offer important results for patients. Trial registration ClinicalTrials.gov NCT02447692 . Prospectively registered on May 19, 2015.

OBJECTIVES:. To describe the rate of failure of the first transition to pressure support ventilation (PSV) after systematic spontaneous awakening trials (SATs) in patients with acute hypoxemic respiratory failure (AHRF) and to assess whether the failure is higher in COVID-19 compared with AHRF of other etiologies. To determine predictors and potential association of failure with outcomes. DESIGN:. Retrospective cohort study. SETTING:. Twenty-eight-bedded medical-surgical ICU in a private hospital (Argentina). PATIENTS:. Subjects with arterial pressure of oxygen (AHRF to Fio2 [Pao2/Fio2] < 300 mm Hg) of different etiologies under controlled mechanical ventilation (MV). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. We collected data during controlled ventilation within 24 hours before SAT followed by the first PSV transition. Failure was defined as the need to return to fully controlled MV within 3 calendar days of PSV start. A total of 274 patients with AHRF (189 COVID-19 and 85 non-COVID-19) were included. The failure occurred in 120 of 274 subjects (43.7%) and was higher in COVID-19 versus non-COVID-19 (49.7% and 30.5%; p = 0.003). COVID-19 diagnosis (odds ratio [OR]: 2.22; 95% CI [1.15–4.43]; p = 0.020), previous neuromuscular blockers (OR: 2.16; 95% CI [1.15–4.11]; p = 0.017) and higher fentanyl dose (OR: 1.29; 95% CI [1.05–1.60]; p = 0.018) increased the failure chances. Higher BMI (OR: 0.95; 95% CI [0.91–0.99]; p = 0.029), Pao2/Fio2 (OR: 0.87; 95% CI [0.78–0.97]; p = 0.017), and pH (OR: 0.61; 95% CI [0.38–0.96]; p = 0.035) were protective. Failure groups had higher 60-day ventilator dependence (p < 0.001), MV duration (p < 0.0001), and ICU stay (p = 0.001). Patients who failed had higher mortality in COVID-19 group (p < 0.001) but not in the non-COVID-19 (p = 0.083). CONCLUSIONS:. In patients with AHRF of different etiologies, the failure of the first PSV attempt was 43.7%, and at a higher rate in COVID-19. Independent risk factors included COVID-19 diagnosis, fentanyl dose, previous neuromuscular blockers, acidosis and hypoxemia preceding SAT, whereas higher BMI was protective. Failure was associated with worse outcomes.

Abstract Background The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. Methods This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008–2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003–2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF

Abstract Background Cardiopulmonary resuscitation (CPR) decreases lung volume below the functional residual capacity and can generate intrathoracic airway closure. Conversely, large insufflations can induce thoracic distension and jeopardize circulation. The capnogram (CO2 signal) obtained during continuous chest compressions can reflect intrathoracic airway closure, and we hypothesized here that it can also indicate thoracic distension. Objectives To test whether a specific capnogram may identify thoracic distension during CPR and to assess the impact of thoracic distension on gas exchange and hemodynamics. Methods (1) In out-of-hospital cardiac arrest patients, we identified on capnograms three patterns: intrathoracic airway closure, thoracic distension or regular pattern. An algorithm was designed to identify them automatically. (2) To link CO2 patterns with ventilation, we conducted three experiments: (i) reproducing the CO2 patterns in human cadavers, (ii) assessing the influence of tidal volume and respiratory mechanics on thoracic distension using a mechanical lung model and (iii) exploring the impact of thoracic distension patterns on different circulation parameters during CPR on a pig model. Measurements and main results (1) Clinical data: 202 capnograms were collected. Intrathoracic airway closure was present in 35%, thoracic distension in 22% and regular pattern in 43%. (2) Experiments: (i) Higher insufflated volumes reproduced thoracic distension CO2 patterns in 5 cadavers. (ii) In the mechanical lung model, thoracic distension patterns were associated with higher volumes and longer time constants. (iii) In six pigs during CPR with various tidal volumes, a CO2 pattern of thoracic distension, but not tidal volume per se, was associated with a significant decrease in blood pressure and cerebral perfusion. Conclusions During CPR, capnograms reflecting intrathoracic airway closure, thoracic distension or regular pattern can be identified. In the animal experiment, a thoracic distension pattern on the capnogram is associated with a negative impact of ventilation on blood pressure and cerebral perfusion during CPR, not predicted by tidal volume per se.

Introduction Titrated application of positive end-expiratory pressure (PEEP) is an important part of any mechanical ventilation strategy. However, the method by which the optimal PEEP is determined and titrated varies widely. Methods for determining optimal PEEP have been assessed using a variety of different study designs and patient populations. We will conduct a scoping review to systematically identify all methods for determining optimal PEEP, and to identify the patient populations, outcomes measured and study designs used for each method. The goal will be to identify gaps in the optimal PEEP literature and identify areas where there may be an opportunity to further systematically synthesise and meta-analyse existing literature.Methods and analysis Using scoping review methodology, we will generate a comprehensive search strategy based on inclusion and exclusion criteria generated using the population, concept, context framework. Five different databases will be searched (MEDLINE, EMBASE, CENTRAL, Web of Science and Scopus). Three investigators will independently screen titles and abstracts, and two investigators will independently complete full-text review and data extraction. Included citations will be categorised in terms of PEEP method, study design, patient population and outcomes measured. The methods for PEEP titration will be described in detail, including strengths and limitations.Ethics and dissemination Given this is a synthesis of existing literature, ethics approval is not required. The results will be disseminated to stakeholders via presentation at local, regional and national levels, as well as publication in a high-impact critical care journal. There is also the potential to impact local clinical care protocols and inform broader clinical practice guidelines undertaken by societies.

Introduction Readiness to be freed from ventilatory support can be evaluated by spontaneous breathing trial (SBT) assessing the patient’s ability to sustain respiratory effort after extubation. Current SBT practices are heterogenous and there are few physiological studies on the topic. The objective of this study is to assess which SBT best reproduces inspiratory effort to breathe after extubation depending on the patient’s illness.Methods and analysis This will be a multicentre randomised cross-over physiological study, in a large population, in the era of modern intensive care units using last generation modern ventilators. Each included patient will perform three 15-minute SBTs in a random order: pressure support ventilation (PSV) level of 7 cmH2O with positive end expiratory pressure (PEEP) level of 0 cmH2O, PSV 0 cmH2O with PEEP 0 cmH2O and T-piece trial. A rest period of baseline state ventilation will be observed between the SBTs (10 min) and before extubation (30 min). Primary outcome will be the inspiratory muscle effort, reflected by pressure time product per minute (PTPmin). This will be calculated from oesophageal pressure measurements at baseline state, before and after each SBT and 20 min after extubation. Secondary outcomes will be PTPmin at 24 hours and 48 hours after extubation, changes in physiological variables and respiratory parameters at each step, postextubation respiratory management and the rate of successful extubation. One hundred patients with at least 24 hours of invasive mechanical ventilation will be analysed, divided into five categories of critical illness: abdominal surgery, brain injury, chest trauma, chronic obstructive pulmonary disease and miscellaneous (pneumonia, sepsis, heart disease).Ethics and dissemination The study project was approved by the appropriate ethics committee (2019-A01063-54, Comité de Protection des Personnes TOURS - Région Centre - Ouest 1, France). Informed consent is required, for all patients or surrogate in case of inability to give consent.Trial registration number NCT04222569.

Abstract Background Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study. Methods The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (FiO2) 40% for 30–120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. Results Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1–49] hours. Only 7 (8%) patients required reintubation. Conclusion The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h.

Abstract Purpose Despite the benefits of mechanical ventilation, its use in critically ill patients is associated with complications and had led to the growth of noninvasive techniques. We assessed the effect of early intubation (first 8 h after vasopressor start) in septic shock patients, as compared to non-early intubated subjects (unexposed), regarding in-hospital mortality, intensive care and hospital length of stay. Methods This study involves secondary analysis of a multicenter prospective study. To adjust for baseline differences in potential confounders, propensity score matching was carried out. In-hospital mortality was analyzed in a time-to-event fashion, while length of stay was assessed as a median difference using bootstrapping. Results A total of 735 patients (137 intubated in the first 8 h) were evaluated. Propensity score matching identified 78 pairs with similar severity and characteristics on admission. Intubation was used in all patients in the early intubation group and in 27 (35%) subjects beyond 8 h in the unexposed group. Mortality occurred in 35 (45%) and in 26 (33%) subjects in the early intubation and unexposed groups (hazard ratio 1.44 95% CI 0.86–2.39, p = 0.16). ICU and hospital length of stay were not different among groups [9 vs. 5 (95% CI 1 to 7) and 14 vs. 16 (95% CI − 7 to 8) days]. All sensitivity analyses confirmed the robustness of our findings. Conclusions An early approach to invasive mechanical ventilation did not improve outcomes in this matched cohort of patients. The limited number of patients included in these analyses out the total number included in the study may limit generalizability of these findings. Trial registration NCT02780466. Registered on May 19, 2016.

Abstract Background Late mortality risk in sepsis-survivors persists for years with high readmission rates and low quality of life. The present study seeks to link the clinical sepsis-survivors heterogeneity with distinct biological profiles at ICU discharge and late adverse events using an unsupervised analysis. Methods In the original FROG-ICU prospective, observational, multicenter study, intensive care unit (ICU) patients with sepsis on admission (Sepsis-3) were identified (N = 655). Among them, 467 were discharged alive from the ICU and included in the current study. Latent class analysis was applied to identify distinct sepsis-survivors clinical classes using readily available data at ICU discharge. The primary endpoint was one-year mortality after ICU discharge. Results At ICU discharge, two distinct subtypes were identified (A and B) using 15 readily available clinical and biological variables. Patients assigned to subtype B (48% of the studied population) had more impaired cardiovascular and kidney functions, hematological disorders and inflammation at ICU discharge than subtype A. Sepsis-survivors in subtype B had significantly higher one-year mortality compared to subtype A (respectively, 34% vs 16%, p

Abstract Background A sequential change in body position from supine-to-both lateral positions under constant ventilatory settings could be used as a postural recruitment maneuver in case of acute respiratory distress syndrome (ARDS), provided that sufficient positive end-expiratory pressure (PEEP) prevents derecruitment. This study aims to evaluate the feasibility and physiological effects of a sequential postural recruitment maneuver in early mechanically ventilated COVID-19 ARDS patients. Methods A cohort of 15 patients receiving lung-protective mechanical ventilation in volume-controlled with PEEP based on recruitability were prospectively enrolled and evaluated in five sequentially applied positions for 30 min each: Supine-baseline; Lateral-1st side; 2nd Supine; Lateral-2nd side; Supine-final. PEEP level was selected using the recruitment-to-inflation ratio (R/I ratio) based on which patients received PEEP 12 cmH2O for R/I ratio ≤ 0.5 or PEEP 15 cmH2O for R/I ratio > 0.5. At the end of each period, we measured respiratory mechanics, arterial blood gases, lung ultrasound aeration, end-expiratory lung impedance (EELI), and regional distribution of ventilation and perfusion using electric impedance tomography (EIT). Results Comparing supine baseline and final, respiratory compliance (29 ± 9 vs 32 ± 8 mL/cmH2O; p

Abstract Background Whether respiratory efforts and their timing can be reliably detected during pressure support ventilation using standard ventilator waveforms is unclear. This would give the opportunity to assess and improve patient–ventilator interaction without the need of special equipment. Methods In 16 patients under invasive pressure support ventilation, flow and pressure waveforms were obtained from proximal sensors and analyzed by three trained physicians and one resident to assess patient’s spontaneous activity. A systematic method (the waveform method) based on explicit rules was adopted. Esophageal pressure tracings were analyzed independently and used as reference. Breaths were classified as assisted or auto-triggered, double-triggered or ineffective. For assisted breaths, trigger delay, early and late cycling (minor asynchronies) were diagnosed. The percentage of breaths with major asynchronies (asynchrony index) and total asynchrony time were computed. Results Out of 4426 analyzed breaths, 94.1% (70.4–99.4) were assisted, 0.0% (0.0–0.2) auto-triggered and 5.8% (0.4–29.6) ineffective. Asynchrony index was 5.9% (0.6–29.6). Total asynchrony time represented 22.4% (16.3–30.1) of recording time and was mainly due to minor asynchronies. Applying the waveform method resulted in an inter-operator agreement of 0.99 (0.98–0.99); 99.5% of efforts were detected on waveforms and agreement with the reference in detecting major asynchronies was 0.99 (0.98–0.99). Timing of respiratory efforts was accurately detected on waveforms: AUC for trigger delay, cycling delay and early cycling was 0.865 (0.853–0.876), 0.903 (0.892–0.914) and 0.983 (0.970–0.991), respectively. Conclusions Ventilator waveforms can be used alone to reliably assess patient’s spontaneous activity and patient–ventilator interaction provided that a systematic method is adopted.

Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation. Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. Findings: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. Interpretation: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. Funding: This work was supported by the UHN Foundation (Grant#1013612).

Abstract Veno-venous extracorporeal membrane oxygenation (ECMO) is a helpful intervention in patients with severe refractory hypoxemia either because mechanical ventilation cannot ensure adequate oxygenation or because lung protective ventilation is not feasible. Since ECMO is a highly invasive procedure with several, potentially devastating complications and its implementation is complex and expensive, simpler and less invasive therapeutic options should be first exploited. Low tidal volume and driving pressure ventilation, prone position, neuromuscular blocking agents and individualized ventilation based on transpulmonary pressure measurements have been demonstrated to successfully treat the vast majority of mechanically ventilated patients with severe hypoxemia. Veno-venous ECMO has a place in the small portion of severely hypoxemic patients in whom these strategies fail. A combined analysis of recent ARDS trials revealed that ECMO was used in only 2.15% of patients (n = 145/6736). Nevertheless, ECMO use has sharply increased in the last decade, raising questions regarding its thoughtful use. Such a policy could be harmful both for patients as well as for the ECMO technique itself. This narrative review attempts to describe together the practical approaches that can be offered to the sickest patients before going to ECMO, as well as the rationale and the limitations of ECMO. The benefit and the drawbacks associated with ECMO use along with a direct comparison with less invasive therapeutic strategies will be analyzed.

Abstract Background Differences in physiology of ARDS have been described between COVID-19 and non-COVID-19 patients. This study aimed to compare initial values and longitudinal changes in respiratory system compliance (C RS), oxygenation parameters and ventilatory ratio (VR) in patients with COVID-19 and non-COVID-19 pulmonary ARDS matched on oxygenation. Methods 135 patients with COVID-19 ARDS from two centers were included in a physiological study; 767 non-COVID-19 ARDS from a clinical trial were used for the purpose of at least 1:2 matching. A propensity-matching was based on age, severity score, oxygenation, positive end-expiratory pressure (PEEP) and pulmonary cause of ARDS and allowed to include 112 COVID-19 and 198 non-COVID pulmonary ARDS. Results The two groups were similar on initial oxygenation. COVID-19 patients had a higher body mass index, higher C RS at day 1 (median [IQR], 35 [28–44] vs 32 [26–38] ml cmH2O−1, p = 0.037). At day 1, C RS was correlated with oxygenation only in non-COVID-19 patients; 61.6% and 68.2% of COVID-19 and non-COVID-19 pulmonary ARDS were still ventilated at day 7 (p = 0.241). Oxygenation became lower in COVID-19 than in non-COVID-19 patients at days 3 and 7, while C RS became similar. VR was lower at day 1 in COVID-19 than in non-COVID-19 patients but increased from day 1 to 7 only in COVID-19 patients. VR was higher at days 1, 3 and 7 in the COVID-19 patients ventilated using heat and moisture exchangers compared to heated humidifiers. After adjustment on PaO2/FiO2, PEEP and humidification device, C RS and VR were found not different between COVID-19 and non-COVID-19 patients at day 7. Day-28 mortality did not differ between COVID-19 and non-COVID-19 patients (25.9% and 23.7%, respectively, p = 0.666). Conclusions For a similar initial oxygenation, COVID-19 ARDS initially differs from classical ARDS by a higher C RS, dissociated from oxygenation. C RS become similar for patients remaining on mechanical ventilation during the first week of evolution, but oxygenation becomes lower in COVID-19 patients. Trial registration: clinicaltrials.gov NCT04385004

Abstract Background We describe a frugal approach (focusing on needs, performance, and costs) to manage a massive influx of COVID-19 patients with acute hypoxemic respiratory failure (AHRF) using the Boussignac valve protected by a filter (“Filter Frugal CPAP”, FF-CPAP) in and out the ICU. Methods (1) A bench study measured the impact of two filters with different mechanical properties on CPAP performances, and pressures were also measured in patients. (2) Non-ICU healthcare staff working in COVID-19 intermediate care units were trained with a video tutorial posted on a massive open online course. (3) A clinical study assessed the feasibility and safety of using FF-CPAP to maintain oxygenation and manage patients out of the ICU during a massive outbreak. Results Bench assessments showed that adding a filter did not affect the effective pressure delivered to the patient. The resistive load induced by the filter variably increased the simulated patient’s work of breathing (6–34%) needed to sustain the tidal volume, depending on the filter’s resistance, respiratory mechanics and basal inspiratory effort. In patients, FF-CPAP achieved pressures similar to those obtained on the bench. The massive training tool provided precious information on the use of Boussignac FF-CPAP on COVID-19 patients. Then 85 COVID-19 patients with ICU admission criteria over a 1-month period were studied upon FF-CPAP initiation for AHRF. FF-CPAP significantly decreased respiratory rate and increased SpO2. Thirty-six (43%) patients presented with respiratory indications for intubation prior to FF-CPAP initiation, and 13 (36%) of them improved without intubation. Overall, 31 patients (36%) improved with FF-CPAP alone and 17 patients (20%) did not require ICU admission. Patients with a respiratory rate > 32 breaths/min upon FF-CPAP initiation had a higher cumulative probability of intubation (p

Abstract Purpose Whether the use of high-flow nasal oxygen in adult patients with COVID-19 associated acute respiratory failure improves clinically relevant outcomes remains unclear. We thus sought to assess the effect of high-flow nasal oxygen on ventilator-free days, compared to early initiation of invasive mechanical ventilation, on adult patients with COVID-19. Methods We conducted a multicentre cohort study using a prospectively collected database of patients with COVID-19 associated acute respiratory failure admitted to 36 Spanish and Andorran intensive care units (ICUs). Main exposure was the use of high-flow nasal oxygen (conservative group), while early invasive mechanical ventilation (within the first day of ICU admission; early intubation group) served as the comparator. The primary outcome was ventilator-free days at 28 days. ICU length of stay and all-cause in-hospital mortality served as secondary outcomes. We used propensity score matching to adjust for measured confounding. Results Out of 468 eligible patients, a total of 122 matched patients were included in the present analysis (61 for each group). When compared to early intubation, the use of high-flow nasal oxygen was associated with an increase in ventilator-free days (mean difference: 8.0 days; 95% confidence interval (CI): 4.4 to 11.7 days) and a reduction in ICU length of stay (mean difference: − 8.2 days; 95% CI − 12.7 to − 3.6 days). No difference was observed in all-cause in-hospital mortality between groups (odds ratio: 0.64; 95% CI: 0.25 to 1.64). Conclusions The use of high-flow nasal oxygen upon ICU admission in adult patients with COVID-19 related acute hypoxemic respiratory failure may lead to an increase in ventilator-free days and a reduction in ICU length of stay, when compared to early initiation of invasive mechanical ventilation. Future studies should confirm our findings.

Abstract Background Reverse triggering (RT) is a dyssynchrony defined by a respiratory muscle contraction following a passive mechanical insufflation. It is potentially harmful for the lung and the diaphragm, but its detection is challenging. Magnitude of effort generated by RT is currently unknown. Our objective was to validate supervised methods for automatic detection of RT using only airway pressure (Paw) and flow. A secondary objective was to describe the magnitude of the efforts generated during RT. Methods We developed algorithms for detection of RT using Paw and flow waveforms. Experts having Paw, flow and esophageal pressure (Pes) assessed automatic detection accuracy by comparison against visual assessment. Muscular pressure (Pmus) was measured from Pes during RT, triggered breaths and ineffective efforts. Results Tracings from 20 hypoxemic patients were used (mean age 65 ± 12 years, 65% male, ICU survival 75%). RT was present in 24% of the breaths ranging from 0 (patients paralyzed or in pressure support ventilation) to 93.3%. Automatic detection accuracy was 95.5%: sensitivity 83.1%, specificity 99.4%, positive predictive value 97.6%, negative predictive value 95.0% and kappa index of 0.87. Pmus of RT ranged from 1.3 to 36.8 cmH20, with a median of 8.7 cmH20. RT with breath stacking had the highest levels of Pmus, and RTs with no breath stacking were of similar magnitude than pressure support breaths. Conclusion An automated detection tool using airway pressure and flow can diagnose reverse triggering with excellent accuracy. RT generates a median Pmus of 9 cmH2O with important variability between and within patients. Trial registration BEARDS, NCT03447288.

Abstract Background In patients intubated for mechanical ventilation, prolonged diaphragm inactivity could lead to weakness and poor outcome. Time to resume a minimal diaphragm activity may be related to sedation practice and patient severity. Methods Prospective observational study in critically ill patients. Diaphragm electrical activity (EAdi) was continuously recorded after intubation looking for resumption of a minimal level of diaphragm activity (beginning of the first 24 h period with median EAdi > 7 µV, a threshold based on literature and correlations with diaphragm thickening fraction). Recordings were collected until full spontaneous breathing, extubation, death or 120 h. A 1 h waveform recording was collected daily to identify reverse triggering. Results Seventy-five patients were enrolled and 69 analyzed (mean age ± standard deviation 63 ± 16 years). Reasons for ventilation were respiratory (55%), hemodynamic (19%) and neurologic (20%). Eight catheter disconnections occurred. The median time for resumption of EAdi was 22 h (interquartile range 0–50 h); 35/69 (51%) of patients resumed activity within 24 h while 4 had no recovery after 5 days. Late recovery was associated with use of sedative agents, cumulative doses of propofol and fentanyl, controlled ventilation and age (older patients receiving less sedation). Severity of illness, oxygenation, renal and hepatic function, reason for intubation were not associated with EAdi resumption. At least 20% of patients initiated EAdi with reverse triggering. Conclusion Low levels of diaphragm electrical activity are common in the early course of mechanical ventilation: 50% of patients do not recover diaphragmatic activity within one day. Sedatives are the main factors accounting for this delay independently from lung or general severity. Trial Registration ClinicalTrials.gov (NCT02434016). Registered on April 27, 2015. First patients enrolled June 2015.

Abstract Background Intensive Care Units (ICU) have sometimes been overwhelmed by the surge of COVID-19 patients. Extending ICU capacity can be limited by the lack of air and oxygen pressure sources available. Transport ventilators requiring only one O2 source may be used in such places. Objective To evaluate the performances of four transport ventilators and an ICU ventilator in simulated severe respiratory conditions. Materials and methods Two pneumatic transport ventilators, (Oxylog 3000, Draeger; Osiris 3, Air Liquide Medical Systems), two turbine transport ventilators (Elisee 350, ResMed; Monnal T60, Air Liquide Medical Systems) and an ICU ventilator (Engström Carestation—GE Healthcare) were evaluated on a Michigan test lung. We tested each ventilator with different set volumes (Vtset = 350, 450, 550 ml) and compliances (20 or 50 ml/cmH2O) and a resistance of 15 cmH2O/l/s based on values described in COVID-19 Acute Respiratory Distress Syndrome. Volume error (percentage of Vtset) with P0.1 of 4 cmH2O and trigger delay during assist-control ventilation simulating spontaneous breathing activity with P0.1 of 4 cmH2O and 8 cmH2O were measured. Results Grouping all conditions, the volume error was 2.9 ± 2.2% for Engström Carestation; 3.6 ± 3.9% for Osiris 3; 2.5 ± 2.1% for Oxylog 3000; 5.4 ± 2.7% for Monnal T60 and 8.8 ± 4.8% for Elisee 350. Grouping all conditions (P0.1 of 4 cmH2O and 8 cmH2O), trigger delay was 50 ± 11 ms, 71 ± 8 ms, 132 ± 22 ms, 60 ± 12 and 67 ± 6 ms for Engström Carestation, Osiris 3, Oxylog 3000, Monnal T60 and Elisee 350, respectively. Conclusions In surge situations such as COVID-19 pandemic, transport ventilators may be used to accurately control delivered volumes in locations, where only oxygen pressure supply is available. Performances regarding triggering function are acceptable for three out of the four transport ventilators tested.

PurposeThere may be a difference in respiratory mechanics, inflammatory markers, and pulmonary emboli in COVID-19 associated ARDS vs. ARDS from other etiologies. Our purpose was to determine differences in respiratory mechanics, inflammatory markers, and incidence of pulmonary embolism in patients with and without COVID-19 associated ARDS admitted in the same period and treated with a similar ventilation strategy.MethodsA cohort study of COVID-19 associated ARDS and non COVID-19 patients in a Saudi Arabian center between June 1 and 15, 2020. We measured respiratory mechanics (ventilatory ratio (VR), recruitability index (RI), markers of inflammation, and computed tomography pulmonary angiograms.ResultsForty-two patients with COVID-19 and 43 non-COVID patients with ARDS comprised the cohort. The incidence of “recruitable” patients using the recruitment/inflation ratio was slightly lower in COVID-19 patients (62 vs. 86%; p = 0.01). Fifteen COVID-19 ARDS patients (35.7%) developed a pulmonary embolism as compared to 4 (9.3%) in other ARDS patients (p = 0.003). In COVID-19 patients, a D-Dimer ≥ 5.0 mcg/ml had a 73% (95% CI 45–92%) sensitivity and 89% (95% CI 71–98%) specificity for predicting pulmonary embolism. Crude 60-day mortality was higher in COVID-19 patients (35 vs. 15%; p = 0.039) but three multivariate analysis showed that independent predictors of 60-day mortality included the ventilatory ratio (OR 3.67, 95% CI 1.61–8.35), PaO2/FIO2 ratio (OR 0.93; 95% CI 0.87–0.99), IL-6 (OR 1.02, 95% CI 1.00–1.03), and D-dimer (OR 7.26, 95% CI 1.11–47.30) but not COVID-19 infection.ConclusionCOVID-19 patients were slightly less recruitable and had a higher incidence of pulmonary embolism than those with ARDS from other etiologies. A high D-dimer was predictive of pulmonary embolism in COVID-19 patients. COVID-19 infection was not an independent predictor of 60-day mortality in the presence of ARDS.

Abstract Background Whether respiratory physiology of COVID-19-induced respiratory failure is different from acute respiratory distress syndrome (ARDS) of other etiologies is unclear. We conducted a single-center study to describe respiratory mechanics and response to positive end-expiratory pressure (PEEP) in COVID-19 ARDS and to compare COVID-19 patients to matched-control subjects with ARDS from other causes. Methods Thirty consecutive COVID-19 patients admitted to an intensive care unit in Rome, Italy, and fulfilling moderate-to-severe ARDS criteria were enrolled within 24 h from endotracheal intubation. Gas exchange, respiratory mechanics, and ventilatory ratio were measured at PEEP of 15 and 5 cmH2O. A single-breath derecruitment maneuver was performed to assess recruitability. After 1:1 matching based on PaO2/FiO2, FiO2, PEEP, and tidal volume, COVID-19 patients were compared to subjects affected by ARDS of other etiologies who underwent the same procedures in a previous study. Results Thirty COVID-19 patients were successfully matched with 30 ARDS from other etiologies. At low PEEP, median [25th–75th percentiles] PaO2/FiO2 in the two groups was 119 mmHg [101–142] and 116 mmHg [87–154]. Average compliance (41 ml/cmH2O [32–52] vs. 36 ml/cmH2O [27–42], p = 0.045) and ventilatory ratio (2.1 [1.7–2.3] vs. 1.6 [1.4–2.1], p = 0.032) were slightly higher in COVID-19 patients. Inter-individual variability (ratio of standard deviation to mean) of compliance was 36% in COVID-19 patients and 31% in other ARDS. In COVID-19 patients, PaO2/FiO2 was linearly correlated with respiratory system compliance (r = 0.52 p = 0.003). High PEEP improved PaO2/FiO2 in both cohorts, but more remarkably in COVID-19 patients (p = 0.005). Recruitability was not different between cohorts (p = 0.39) and was highly inter-individually variable (72% in COVID-19 patients and 64% in ARDS from other causes). In COVID-19 patients, recruitability was independent from oxygenation and respiratory mechanics changes due to PEEP. Conclusions Early after establishment of mechanical ventilation, COVID-19 patients follow ARDS physiology, with compliance reduction related to the degree of hypoxemia, and inter-individually variable respiratory mechanics and recruitability. Physiological differences between ARDS from COVID-19 and other causes appear small.

Abstract Background Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2

Objective: Assessing the respiratory and lung mechanics of the patients in intensive care units is of utmost need in order to guide the management of ventilation support. The esophageal pressure (Peso) signal is a minimally invasive measure, which portrays the mechanics of the lung and the pattern of breathing. Because of the close proximity of the lung to the beating heart inside the thoracic cavity, the Peso signals always get contaminated with that of the oscillatory-pressure-signal of the heart, which is known as the cardiogenic oscillation (CGO) signal. However, the area of research addressing the removal of CGO from Peso signal is still lagging behind. Methods and results: This paper presents a singular spectrum analysis-based high-efficient, adaptive and robust technique for the removal of CGO from Peso signal utilizing the inherent periodicity and morphological property of the Peso signal. The performance of the proposed technique is tested on Peso signals collected from the patients admitted to the intensive care unit, cadavers, and also on synthetic Peso signals. The efficiency of the proposed technique in removing CGO from the Peso signal is quantified through both qualitative and quantitative measures, and the mean opinion scores of the denoised Peso signal fall under the categories `very good' as per the subjective measure. Conclusion and clinical impact: The proposed technique: (1) does not follow any predefined mathematical model and hence, it is data-driven, (2) is adaptive to the sampling rate, and (3) can be adapted for denoising other biomedical signals which exhibit periodic or quasi-periodic nature.

Background: Respiratory muscle electromyography (EMG) can identify whether a muscle is activated, its activation amplitude, and timing. Most studies have focused on the activation amplitude, while differences in timing and duration of activity have been less investigated. Detection of the timing of respiratory muscle activity is typically based on the visual inspection of the EMG signal. This method is time-consuming and prone to subjective interpretation.Aims: Our main objective was to develop and validate a method to assess the respective timing of different respiratory muscle activity in an objective and semi-automated manner.Method: Seven healthy adults performed an inspiratory threshold loading (ITL) test at 50% of their maximum inspiratory pressure until task failure. Surface EMG recordings of the costal diaphragm/intercostals, scalene, parasternal intercostals, and sternocleidomastoid were obtained during ITL. We developed a semi-automated algorithm to detect the onset (EMG, onset) and offset (EMG, offset) of each muscle’s EMG activity breath-by-breath with millisecond accuracy and compared its performance with manual evaluations from two independent assessors. For each muscle, the Intraclass Coefficient correlation (ICC) of the EMG, onset detection was determined between the two assessors and between the algorithm and each assessor. Additionally, we explored muscle differences in the EMG, onset, and EMG, offset timing, and duration of activity throughout the ITL.Results: More than 2000 EMG, onset s were analyzed for algorithm validation. ICCs ranged from 0.75–0.90 between assessor 1 and 2, 0.68–0.96 between assessor 1 and the algorithm, and 0.75–0.91 between assessor 2 and the algorithm (p 0.63).Conclusion: We developed an algorithm to detect EMG, onset of several respiratory muscles with millisecond accuracy that is time-efficient and validated against manual measures. Compared to the inherent bias of manual measures, the algorithm enhances objectivity and provides a strong standard for determining the respiratory muscle EMG, onset.

Abstract Background Non-invasive ventilation (NIV) is preferred as the initial ventilatory support to treat acute hypercapnic respiratory failure in patients with chronic obstructive pulmonary disease (COPD). High-flow nasal cannula (HFNC) may be an alternative method; however, the effects of HFNC in hypercapnic COPD are not well known. This preliminary study aimed at assessing the physiologic effects of HFNC at different flow rates in hypercapnic COPD and to compare it with NIV. Methods A prospective physiologic study enrolled 12 hypercapnic COPD patients who had initially required NIV, and were ventilated with HFNC at flow rates increasing from 10 to 50 L/min for 15 min in each step. The primary outcome was the effort to breathe estimated by a simplified esophageal pressure–time product (sPTPes). The other studied variables were respiratory rate, oxygen saturation (SpO2), and transcutaneous CO2 pressure (PtcCO2). Results Before NIV initiation, the median [interquartile range] pH was 7.36 [7.28–7.37] with a PaCO2 of 51 [42–60] mmHg. sPTPes per minute was significantly lower with HFNC at 30 L/min than 10 and 20 L/min (p

Abstract Background The electrical activity of the crural diaphragm (Eadi), a surrogate of respiratory drive, can now be measured at the bedside in mechanically ventilated patients with a specific catheter. The expected range of Eadi values under stressed or assisted spontaneous breathing is unknown. This study explored Eadi values in healthy subjects during unstressed (baseline), stressed (with a resistance) and assisted spontaneous breathing. The relation between Eadi and inspiratory effort was analyzed. Methods Thirteen healthy male volunteers were included in this randomized crossover study. Eadi and esophageal pressure (Peso) were recorded during unstressed and stressed spontaneous breathing and under assisted ventilation delivered in pressure support (PS) at low and high assist levels and in neurally adjusted ventilatory assist (NAVA). Overall eight different situations were assessed in each participant (randomized order). Peak, mean and integral of Eadi, breathing pattern, esophageal pressure–time product (PTPeso) and work of breathing (WOB) were calculated offline. Results Median [interquartile range] peak Eadi at baseline was 17 [13–22] μV and was above 10 μV in 92% of the cases. Eadimax defined as Eadi measured at maximal inspiratory capacity reached 90 [63 to 99] μV. Median peak Eadi/Eadimax ratio was 16.8 [15.6–27.9]%. Compared to baseline, respiratory rate and minute ventilation were decreased during stressed non-assisted breathing, whereas peak Eadi and PTPeso were increased. During unstressed assisted breathing, peak Eadi decreased during high-level PS compared to unstressed non-assisted breathing and to NAVA (p = 0.047). During stressed breathing, peak Eadi was lower during all assisted ventilation modalities compared to stressed non-assisted breathing. During assisted ventilation, across the different conditions, peak Eadi changed significantly, whereas PTPeso and WOB/min were not significantly modified. Finally, Eadi signal was still present even when Peso signal was suppressed due to high assist levels. Conclusion Eadi analysis provides complementary information compared to respiratory pattern and to Peso monitoring, particularly in the presence of high assist levels. Trial registration The study was registered as NCT01818219 in clinicaltrial.gov. Registered 28 February 2013

Abstract Fifteen recommendations and a therapeutic algorithm regarding the management of acute respiratory distress syndrome (ARDS) at the early phase in adults are proposed. The Grade of Recommendation Assessment, Development and Evaluation (GRADE) methodology has been followed. Four recommendations (low tidal volume, plateau pressure limitation, no oscillatory ventilation, and prone position) had a high level of proof (GRADE 1 + or 1 −); four (high positive end-expiratory pressure [PEEP] in moderate and severe ARDS, muscle relaxants, recruitment maneuvers, and venovenous extracorporeal membrane oxygenation [ECMO]) a low level of proof (GRADE 2 + or 2 −); seven (surveillance, tidal volume for non ARDS mechanically ventilated patients, tidal volume limitation in the presence of low plateau pressure, PEEP > 5 cmH2O, high PEEP in the absence of deleterious effect, pressure mode allowing spontaneous ventilation after the acute phase, and nitric oxide) corresponded to a level of proof that did not allow use of the GRADE classification and were expert opinions. Lastly, for three aspects of ARDS management (driving pressure, early spontaneous ventilation, and extracorporeal carbon dioxide removal), the experts concluded that no sound recommendation was possible given current knowledge. The recommendations and the therapeutic algorithm were approved by the experts with strong agreement.

Abstract Background In addition to the risk of developing ventilator-induced lung injury, patients with ARDS are at risk of developing hyperoxic injury due the supra-physiological oxygen supplementation clinically required to reverse hypoxemia. Alterations of endogenous surfactant system participate in the pulmonary dysfunction observed in ARDS. Administration of exogenous surfactant could have protective effects during hyperoxia. Methods Male BALB/c mice (8–10 weeks), a strain highly sensitive to hyperoxia, received the exogenous surfactant-containing protein SP-B and SP-C by intranasal instillation 12 h before starting 24 h of exposure to hyperoxia in an inhalation chamber and were compared to mice receiving hyperoxia alone and to controls subjected to normoxia. Results Compared to the hyperoxia group, the administration of exogenous surfactant was able to reduce lung inflammation through a reduction in the influx of neutrophils and inflammatory biomarkers such as TNF, IL-17, and HMGB1 expression. The antioxidant activity prevented oxidative damage by reducing lipid peroxidation and protein carbonylation and increasing superoxide dismutase activity when compared to the hyperoxia group. Conclusion Our results offer new perspectives on the effects and the mechanism of exogenous surfactant in protecting the airway and lungs, in oxygen-rich lung microenvironment, against oxidative damage and aggravation of acute inflammation induced by hyperoxia.

Background Oesophageal pressure (Poes) is used to approximate pleural pressure (Ppl) and therefore to estimate transpulmonary pressure (PL). We aimed to compare oesophageal and regional pleural pressures and to calculate transpulmonary pressures in a prospective physiological study on lung transplant recipients during their stay in the intensive care unit of a tertiary university hospital. Methods Lung transplant recipients receiving invasive mechanical ventilation and monitored by oesophageal manometry and dependent and nondependent pleural catheters were investigated during the post-operative period. We performed simultaneous short-time measurements and recordings of oesophageal manometry and pleural pressures. Expiratory and inspiratory PL were computed by subtracting regional Ppl or Poes from airway pressure; inspiratory PL was also calculated with the elastance ratio method. Results 16 patients were included. Among them, 14 were analysed. Oesophageal pressures correlated with dependent and nondependent pleural pressures during expiration (R2=0.71, p=0.005 and R2=0.77, p=0.001, respectively) and during inspiration (R2=0.66 for both, p=0.01 and p=0.014, respectively). PL values calculated using Poes were close to those obtained from the dependent pleural catheter but higher than those obtained from the nondependent pleural catheter both during expiration and inspiration. Conclusions In ventilated lung transplant recipients, oesophageal manometry is well correlated with pleural pressure. The absolute value of Poes is higher than Ppl of nondependent lung regions and could therefore underestimate the highest level of lung stress in those at high risk of overinflation.

Delirium is a syndrome characterized by acute brain failure resulting in neurocognitive disturbances affecting attention, awareness, and cognition. It is highly prevalent among critically ill patients and is associated with increased morbidity and mortality. A core domain of delirium is represented by behavioral disturbances in sleep-wake cycle probably related to circadian rhythm disruption. The relationship between sleep, circadian rhythm and intensive care unit (ICU)-acquired delirium is complex and likely bidirectional. In this review, we explore the proposed pathophysiological mechanisms of sleep disruption and circadian dysrhythmia as possible contributing factors in transitioning to delirium in the ICU and highlight some of the most relevant caveats for understanding the relationship between these complex phenomena. Specifically, we will (1) review the physiological consequences of poor sleep quality and efficiency; (2) explore how the neural substrate underlying the circadian clock functions may be disrupted in delirium; (3) discuss the role of sedative drugs as contributors to delirium and chrono-disruption; and, (4) describe the association between abnormal sleep-pathological wakefulness, circadian dysrhythmia, delirium and critical illness. Opportunities to improve sleep and readjust circadian rhythmicity to realign the circadian clock may exist as therapeutic targets in both the prevention and treatment of delirium in the ICU. Further research is required to better define these conditions and understand the underlying physiologic relationship to develop effective prevention and therapeutic strategies.

Abstract Background Noninvasive ventilation (NIV) is the first-line treatment of adult patients with exacerbations of cystic fibrosis (CF). High-flow nasal oxygen therapy (HFNT) might benefit patients with hypoxemia and can reduce physiological dead space. We hypothesized that HFNT and NIV would similarly reduce work of breathing and improving breathing pattern in CF patients. Our objective was to compare the effects of HFNT versus NIV in terms of work of breathing, assessed noninvasively by the thickening fraction of the diaphragm (TFdi, measured with ultrasound), breathing pattern, transcutaneous CO2 (PtcCO2), hemodynamics, dyspnea and comfort. Methods Adult CF patients who had been stabilized after requiring ventilatory support for a few days were enrolled and ventilated with HFNT and NIV for 30 min in crossover random order. Results Fifteen patients were enrolled. Compared to baseline, HFNT, but not NIV, reduced respiratory rate (by 3 breaths/min, p = 0.01) and minute ventilation (by 2 L/min, p = 0.01). Patients also took slightly larger tidal volumes with HFNT compared to NIV (p = 0.02). TFdi per breath was similar under the two techniques and did not change from baseline. MAP increased from baseline with NIV and compared to HFNT (p ≤ 0.01). Comfort was poorer with the application of both HFNT and NIV than baseline. No differences were found for heart rate, SpO2, PtcCO2 or dyspnea. Conclusions In adult CF patients stabilized after indication for ventilatory support, HFNT and NIV have similar effects on diaphragmatic work per breath, but high-flow therapy confers additional physiological benefits by decreasing respiratory rate and minute ventilation. Clinical trial registration Ethics Committee of St. Michael’s Hospital (REB #14-338) and clinicaltrial.gov (NCT02262871).

Abstract Background Adding cyclic short sustained inflations (sigh) to assisted ventilation yields optimizes lung recruitment, decreases heterogeneity and reduces inspiratory effort in patients with acute hypoxemic respiratory failure (AHRF). These findings suggest that adding sigh to pressure support ventilation (PSV) might decrease the risk of lung injury, shorten weaning and improve clinical outcomes. Thus, we conceived a pilot trial to test the feasibility of adding sigh to PSV (the PROTECTION study). Methods PROTECTION is an international randomized controlled trial that will be conducted in 23 intensive care units (ICUs). Patients with AHRF who have been intubated from 24 h to 7 days and undergoing PSV from 4 to 24 h will be enrolled. All patients will first undergo a 30-min sigh test by adding sigh to clinical PSV for 30 min to identify early oxygenation responders. Then, patients will be randomized to PSV or PSV + sigh until extubation, ICU discharge, death or day 28. Sigh will be delivered as a 3-s pressure control breath delivered once per minute at 30 cmH2O. Standardized protocols will guide ventilation settings, switch back to controlled ventilation, use of rescue treatments, performance of spontaneous breathing trial, extubation and reintubation. The primary endpoint of the study will be to verify the feasibility of PSV + sigh evaluated through reduction of failure to remain on assisted ventilation during the first 28 days in the PSV + sigh group versus standard PSV (15 vs. 22%). Failure will be defined by switch back to controlled ventilation for more than 24 h or use of rescue treatments or reintubation within 48 h from elective extubation. Setting the power to 80% and first-risk order to 5%, the computed size of the trial is 129 patients per arm. Discussion PROTECTION is a pilot randomized controlled trial testing the feasibility of adding sigh to PSV. If positive, it will provide physicians with an effective addition to standard PSV for lung protection, able to reduce failure of assisted ventilation. PROTECTION will provide the basis for a future larger trial aimed at verifying the impact of PSV + sigh on 28-day survival and ventilator-free days. Trial registration ClinicalTrials.gov, NCT03201263. Registered on 28 June 2017.

Abstract Background Cardiac dysfunction is a common cause of weaning failure. Weaning shares some similarities with a cardiac stress test and may challenge active phases of the cardiac cycle-like ventricular contractility and relaxation. This study aimed at assessing systolic and diastolic function during the weaning process and scrutinizing their dynamics during weaning trials. Methods Echocardiography was performed during baseline ventilator settings to assess cardiac function at the initiation of the weaning process and at the start and the end of consecutive weaning trials (performed at day-1, day-2, and before extubation if applicable) to explore the evolution of left ventricle contractility and relaxation in a subset of patients. Results Among 67 patients included, weaning was prolonged (≥ 7 days) in 18 (27%) patients and short (

Abstract In this review, we seek to highlight how critical illness and critical care affect longer-term outcomes, to underline the contribution of ICU delirium to cognitive dysfunction several months after ICU discharge, to give new insights into ICU acquired weakness, to emphasize the importance of value-based healthcare, and to delineate the elements of family-centered care. This consensus of 29 also provides a perspective and a research agenda about post-ICU recovery.

Abstract Background In pressure-controlled (PC) ventilation, tidal volume (V T) and transpulmonary pressure (P L ) result from the addition of ventilator pressure and the patient’s inspiratory effort. PC modes can be classified into fully, partially, and non-synchronized modes, and the degree of synchronization may result in different V T and P L despite identical ventilator settings. This study assessed the effects of three PC modes on V T, P L , inspiratory effort (esophageal pressure–time product, PTPes), and airway occlusion pressure, P 0.1. We also assessed whether P 0.1 can be used for evaluating patient effort. Methods Prospective, randomized, crossover physiologic study performed in 14 spontaneously breathing mechanically ventilated patients recovering from acute respiratory failure (1 subsequently withdrew). PC modes were fully (PC-CMV), partially (PC-SIMV), and non-synchronized (PC-IMV using airway pressure release ventilation) and were applied randomly; driving pressure, inspiratory time, and set respiratory rate being similar for all modes. Airway, esophageal pressure, P 0.1, airflow, gas exchange, and hemodynamics were recorded. Results V T was significantly lower during PC-IMV as compared with PC-SIMV and PC-CMV (387 ± 105 vs 458 ± 134 vs 482 ± 108 mL, respectively; p

Abstract Acute respiratory distress syndrome (ARDS) is a common condition in intensive care unit patients and remains a major concern, with mortality rates of around 30–45% and considerable long-term morbidity. Respiratory support in these patients must be optimized to ensure adequate gas exchange while minimizing the risks of ventilator-induced lung injury. The aim of this expert opinion document is to review the available clinical evidence related to ventilator support and adjuvant therapies in order to provide evidence-based and experience-based clinical recommendations for the management of patients with ARDS.

Abstract Background Patients meeting the Berlin definition for the acute respiratory distress syndrome (ARDS) might lack exposure to one or more “common” risk factors and exhibit different clinical phenotype and outcomes. We aimed to compare the clinical presentation and outcome of ARDS patients with or without risk factors, the impact on hospital mortality, and to assess the diagnostic work-up performed. The current study is an ancillary analysis of an international, multicenter, prospective cohort study (the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure, LUNG SAFE). Patients meeting ARDS criteria within 2 days of acute hypoxemic respiratory failure onset were included in the study and categorized as having risk factors or not. Outcomes were compared using propensity score matching. Results Among 2813 patients, 234 (8.3% [7.3–9.3]) had no ARDS risk factor identified. These were older, had more frequent chronic diseases and presented with less severe SOFA and non-pulmonary SOFA scores (p 0.99). Among ARDS with no risk factor, 45 patients (19.2%) had a specific diagnosis made. As compared to others, patients having ARDS with no risk factor had a lower ICU but not hospital mortality (34.6 vs 40.0%; p = 0.12). A matched cohort analysis confirmed the lack of significant difference in mortality. Conclusion Eight percent of ARDS patients have no identified risk factor, 80% of whom have no etiological diagnosis made. The outcome of ARDS with no risk factor was comparable to other ARDS but few had a comprehensive diagnostic work-up, potentially leading to missed curable diseases. Trial registration clinicaltrials.gov Identifier: NCT02010073