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Background: The antiinflammatory effects of hydrogen sulfide (H2S) and sodium sulfide (Na2S) treatment may prevent acute lung injury induced by high tidal volume (HVT) ventilation. However, lung protection may be limited by direct pulmonary toxicity associated with H2S inhalation. Therefore, the authors tested whether the inhalation of H2S or intravascular Na2S treatment can protect against ventilator-induced lung injury in mice.Methods: Anesthetized mice continuously inhaled 0, 1, 5, or 60 ppm H2S or received a single bolus infusion of Na2S (0.55 mg/kg) or vehicle and were then subjected to HVT (40 ml/kg) ventilation lasting 4 h (n = 4-8 per group).Results: HVT ventilation increased the concentrations of protein and interleukin-6 in bronchoalveolar lavage fluid, contributing to reduced respiratory compliance and impaired arterial oxygenation, and caused death from lung injury and pulmonary edema. Inhalation of 1 or 5 ppm H2S during HVT ventilation did not alter lung injury, but inhalation of 60 ppm H2S accelerated the development of ventilator-induced lung injury and enhanced the pulmonary expression of the chemoattractant CXCL-2 and the leukocyte adhesion molecules CD11b and L-selectin. In contrast, pretreatment with Na2S attenuated the expression of CXCL-2 and CD11b during HVT ventilation and reduced pulmonary edema. Moreover, Na2S enhanced the pulmonary expression of Nrf2-dependent antioxidant genes (NQO1, GPX2, and GST-A4) and prevented oxidative stress-induced depletion of glutathione in lung tissue.Conclusions: The data suggest that systemic intravascular treatment with Na2S represents a novel therapeutic strategy to prevent both ventilator-induced lung injury and pulmonary glutathione depletion by activating Nrf2-dependent antioxidant gene transcription. [ABSTRACT FROM AUTHOR]

Objective: During pressure support ventilation (PS), an abrupt increase in ventilator pressure above the pre-set level is considered to signify expiratory muscle activity. However, relaxation of inspiratory muscles may also cause the same phenomenon, and this hypothesis has not been explored. The aim of this study is to examine the cause of this increase in ventilator pressure, during PS, in critically ill patients.Design: Retrospective study.Setting: In a university intensive care unit.Methods: Fifteen patients instrumented with esophageal and gastric balloons, and in whom airway pressure (P (aw)) during PS exhibited an acute increase above the pre-set level towards the end of mechanical inspiration were retrospectively analyzed. For each breath, the time of the rapid increase in P (aw) was identified (t (Paw)) and, using the transdiaphragmatic (P (di)) and gastric (P (ga)) pressure waveforms, related to: (1) the end of neural inspiration (peak P (di)) and (2) the time at which P (ga) started to increase rapidly after the end of neural inspiration indicating expiratory muscle recruitment.Results: The t (Paw) was observed 32+/-34ms after the end of neural inspiration, well before (323+/-182ms) expiratory muscle recruitment (identified in eight patients). There was a significant linear relationship between the rate of rise of P (aw) after t (Paw) and the rates of decline of P (di) and inspiratory flow.Conclusion: We conclude that, during PS ventilation, the relaxation of inspiratory muscles accounts for the acute increase in P (aw) above the pre-set level, in addition to the contribution made by the occurrence of expiratory muscle activity. [ABSTRACT FROM AUTHOR]

Rationale: Because of the effects of aging on the respiratory system, it is conceivable that the association between driving pressure and mortality depends on age. Objectives: We endeavored to evaluate whether the association between driving pressure and mortality of patients with acute respiratory distress syndrome (ARDS) varies across the adult lifespan, hypothesizing that it is stronger in older, including very old (⩾80 yr), patients. Methods: We performed a secondary analysis of individual patient-level data from seven ARDS Network and PETAL Network randomized controlled trials ("ARDSNet cohort"). We tested our hypothesis in a second, independent, national cohort ("Hellenic cohort"). We performed both binary logistic and Cox regression analyses including the interaction term between age (as a continuous variable) and driving pressure at baseline (i.e., the day of trial enrollment) as the predictor and 90-day mortality as the dependent variable. Measurements and Main Results: On the basis of data from 4,567 patients with ARDS included in the ARDSNet cohort, we found that the effect of driving pressure on mortality depended on age ( P  = 0.01 for the interaction between age as a continuous variable and driving pressure). The difference in driving pressure between survivors and nonsurvivors significantly changed across the adult lifespan ( P  < 0.01). In both cohorts, a driving pressure threshold of 11 cm H 2 O was associated with mortality in very old patients. Conclusions: Data from randomized controlled trials with strict inclusion criteria suggest that the effect of driving pressure on the mortality of patients with ARDS may depend on age. These results may advocate for a personalized age-dependent mechanical ventilation approach.

Background: Patient-ventilator dyssynchrony is frequently observed during assisted mechanical ventilation. However, the effects of expiratory muscle contraction on patient-ventilator interaction are underexplored. The authors hypothesized that active expiration would affect patient-ventilator interaction and they tested their hypothesis in a mixed cohort of invasively ventilated patients with spontaneous breathing activity., Methods: This is a retrospective observational study involving patients on assisted mechanical ventilation who had their esophageal pressure (Peso) and gastric pressure monitored for clinical purposes. Active expiration was defined as gastric pressure rise (ΔPgas) greater than or equal to 1.0 cm H2O during expiratory flow without a corresponding change in diaphragmatic pressure. Waveforms of Peso, gastric pressure, diaphragmatic pressure, flow, and airway pressure (Paw) were analyzed to identify and characterize abnormal patient-ventilator interaction., Results: 76 patients were identified with Peso and gastric pressure recordings, of whom 58 demonstrated active expiration with a median ΔPgas of 3.4 cm H2O (interquartile range = 2.4 to 5.3) observed in this subgroup. Among these 58 patients, 23 presented the following events associated with expiratory muscle activity: (1) distortions in Paw and flow that resembled ineffective efforts, (2) distortions similar to autotriggering, (3) multiple triggering, (4) prolonged ventilatory cycles with biphasic inspiratory flow, with a median percentage (interquartile range) increase in mechanical inflation time and tidal volume of 54% (44 to 70%) and 25% (8 to 35%), respectively and (5) breathing exclusively by expiratory muscle relaxation. Gastric pressure monitoring was required to identify the association of active expiration with these events. Respiratory drive, assessed by the rate of inspiratory Peso decrease, was significantly higher in patients with active expiration (median [interquartile range] dPeso/dt: 12.7 [9.0 to 18.5] vs 9.2 [6.8 to 14.2] cmH2O/sec; P < 0.05)., Conclusions: Active expiration can impair patient-ventilator interaction in critically ill patients. Without documenting gastric pressure, abnormal patient-ventilator interaction associated with expiratory muscle contraction may be mistakenly attributed to a mismatch between the patient's inspiratory effort and mechanical inflation. This misinterpretation could potentially influence decisions regarding clinical management., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Data on COVID-19 mortality among patients in intensive care units (ICUs) from Eastern and/or Southern European countries, including Greece, are limited. The purpose of this study was to evaluate the ICU mortality trends among critically ill COVID-19 patients during the first two years of the pandemic in Greece and to further investigate if certain patients' clinical characteristics contributed to this outcome. We conducted a multi-center retrospective observational study among five large university hospitals in Greece, between February 2020 and January 2022. All adult critically ill patients with confirmed COVID-19 disease who required ICU admission for at least 24 h were eligible. In total, 1462 patients (66.35% males) were included in this study. The mean age of this cohort was 64.9 (±13.27) years old. The 28-day mortality rate was 35.99% ( n = 528), while the overall in-hospital mortality was 50.96% ( n = 745). Cox regression analysis demonstrated that older age (≥65 years old), a body mass index within the normal range, and a delay in ICU admission from symptom onset, as well as worse baseline clinical severity scores upon ICU admission, were associated with a greater risk of death. Mortality of critically ill COVID-19 patients was high during the first two years of the pandemic in Greece but comparable to other countries. Risk factors for death presented in this study are not different from those that have already been described for COVID-19 in other studies.

The limited reserves of neutrophils are implicated in the susceptibility to infection in neonates, however the regulation of neutrophil kinetics in infections in early life remains poorly understood. Here we show that the developmental endothelial locus (DEL-1) is elevated in neonates and is critical for survival from neonatal polymicrobial sepsis, by supporting emergency granulopoiesis. Septic DEL-1 deficient neonate mice display low numbers of myeloid-biased multipotent and granulocyte-macrophage progenitors in the bone marrow, resulting in neutropenia, exaggerated bacteremia, and increased mortality; defects that are rescued by DEL-1 administration. A high IL-10/IL-17A ratio, observed in newborn sepsis, sustains tissue DEL-1 expression, as IL-10 upregulates while IL-17 downregulates DEL-1. Consistently, serum DEL-1 and blood neutrophils are elevated in septic adult and neonate patients with high serum IL-10/IL-17A ratio, and mortality is lower in septic patients with high serum DEL-1. Therefore, IL-10/DEL-1 axis supports emergency granulopoiesis, prevents neutropenia and promotes sepsis survival in early life., (© 2024. The Author(s).)

Background: During control mechanical ventilation (CMV), the driving pressure of the respiratory system (ΔP rs ) serves as a surrogate of transpulmonary driving pressure (ΔP lung ). Expiratory muscle activity that decreases end-expiratory lung volume may impair the validity of ΔP rs to reflect ΔP lung . This prospective observational study in patients with acute respiratory distress syndrome (ARDS) ventilated with proportional assist ventilation (PAV+), aimed to investigate: (1) the prevalence of elevated ΔP lung , (2) the ΔP rs -ΔP lung relationship, and (3) whether dynamic transpulmonary pressure (Plung sw ) and effort indices (transdiaphragmatic and respiratory muscle pressure swings) remain within safe limits., Methods: Thirty-one patients instrumented with esophageal and gastric catheters (n = 22) were switched from CMV to PAV+ and respiratory variables were recorded, over a maximum of 24 h. To decrease the contribution of random breaths with irregular characteristics, a 7-breath moving average technique was applied. In each patient, measurements were also analyzed per deciles of increasing lung elastance (E lung ). Patients were divided into Group A, if end-inspiratory transpulmonary pressure (P LEI ) increased as E lung increased, and Group B, which showed a decrease or no change in P LEI with E lung increase., Results: In 44,836 occluded breaths, ΔP lung  ≥ 12 cmH 2 O was infrequently observed [0.0% (0.0-16.9%) of measurements]. End-expiratory lung volume decrease, due to active expiration, was associated with underestimation of ΔP lung by ΔP rs , as suggested by a negative linear relationship between transpulmonary pressure at end-expiration (P LEE ) and ΔP lung /ΔP rs . Group A included 17 and Group B 14 patients. As E lung increased, ΔP lung increased mainly due to P LEI increase in Group A, and P LEE decrease in Group B. Although ΔP rs had an area receiver operating characteristic curve (AUC) of 0.87 (95% confidence intervals 0.82-0.92, P < 0.001) for ΔP lung  ≥ 12 cmH 2 O, this was due exclusively to Group A [0.91 (0.86-0.95), P < 0.001]. In Group B, ΔP rs showed no predictive capacity for detecting ΔP lung  ≥ 12 cmH 2 O [0.65 (0.52-0.78), P > 0.05]. Most of the time Plung sw and effort indices remained within safe range., Conclusion: In patients with ARDS ventilated with PAV+, injurious tidal lung stress and effort were infrequent. In the presence of expiratory muscle activity, ΔP rs underestimated ΔP lung . This phenomenon limits the usefulness of ΔP rs as a surrogate of tidal lung stress, regardless of the mode of support., (© 2024. The Author(s).)

Background: The Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and edema, impairing both oxygenation and lung compliance. Recent studies reported a dissociation between oxygenation and compliance (severe hypoxemia with preserved compliance) in early ARDS and COVID-19-related-ARDS (CARDS). During the pandemic, in patients requiring prolonged mechanical ventilation, we observed the opposite combination (mild-moderate hypoxemia but significantly impaired compliance). The purpose of our study was to investigate the prevalence of this combination of mild-moderate hypoxemia and impaired compliance in persistent ARDS and CARDS., Methods: For this retrospective study, we used individual patient-level data from two independent cohorts of ARDS patients. The ARDSNet cohort included patients from four ARDS Network randomized controlled trials. The CARDS cohort included patients with ARDS due to COVID-19 hospitalized in two intensive care units in Greece. We used a threshold of 150 for PaO 2 /FiO 2 and 30 ml/cmH 2 O for compliance, estimated the prevalence of each of the four combinations of oxygenation and compliance at baseline, and examined the change in its prevalence from baseline to day 21 in the ARDSNet and CARDS cohorts., Results: The ARDSNet cohort included 2909 patients and the CARDS cohort included 349 patients. The prevalence of the combination of mild-moderate hypoxemia and low compliance increased from baseline to day 21 both in the ARDSNet cohort (from 22.2 to 42.7%) and in the CARDS cohort (from 3.1 to 33.3%). Among surviving patients with low compliance, oxygenation improved over time. The 60-day mortality rate was higher for patients who had mild-moderate hypoxemia and low compliance on day 21 (28% and 56% in ARDSNet and CARDS), compared to those who had mild-moderate hypoxemia and high compliance (20% and 50%, respectively)., Conclusions: Among patients with ARDS who require prolonged controlled mechanical ventilation, regardless of ARDS etiology, a dissociation between oxygenation and compliance characterized by mild-moderate hypoxemia but low compliance becomes increasingly prevalent. The findings of this study highlight the importance of monitoring mechanics in patients with persistent ARDS., (© 2023. The Author(s).)

Hiccups-like contractions, including hiccups, respiratory myoclonus, and diaphragmatic tremor, refer to involuntary, spasmodic, and inspiratory muscle contractions. They have been repeatedly described in mechanically ventilated patients, especially those with central nervous damage. Nevertheless, their effects on patient-ventilator interaction are largely unknown, and even more overlooked is their contribution to lung and diaphragm injury. We describe, for the first time, how the management of hiccup-like contractions was individualized based on esophageal and transpulmonary pressure measurements in three mechanically ventilated patients. The necessity or not of intervention was determined by the effects of these contractions on arterial blood gases, patient-ventilator synchrony, and lung stress. In addition, esophageal pressure permitted the titration of ventilator settings in a patient with hypoxemia and atelectasis secondary to hiccups and in whom sedatives failed to eliminate the contractions and muscle relaxants were contraindicated. This report highlights the importance of esophageal pressure monitoring in the clinical decision making of hiccup-like contractions in mechanically ventilated patients.

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., (© 2023. The Author(s).)

During pressure support ventilation (PSV), excessive assist results in weak inspiratory efforts and promotes diaphragm atrophy and delayed weaning. The aim of this study was to develop a classifier using a neural network to identify weak inspiratory efforts during PSV, based on the ventilator waveforms. Recordings of flow, airway, esophageal and gastric pressures from critically ill patients were used to create an annotated dataset, using data from 37 patients at 2-5 different levels of support, computing the inspiratory time and effort for every breath. The complete dataset was randomly split, and data from 22 patients (45,650 breaths) were used to develop the model. Using a One-Dimensional Convolutional Neural Network, a predictive model was developed to characterize the inspiratory effort of each breath as weak or not, using a threshold of 50 cmH 2 O*s/min. The following results were produced by implementing the model on data from 15 different patients (31,343 breaths). The model predicted weak inspiratory efforts with a sensitivity of 88%, specificity of 72%, positive predictive value of 40%, and negative predictive value of 96%. These results provide a 'proof-of-concept' for the ability of such a neural-network based predictive model to facilitate the implementation of personalized assisted ventilation.

Background: The risk of inflammatory diseases is sex-dependent, but it remains unknown whether this is due to the impact of sex hormones or sex chromosomes. Transgender individuals represent a unique cohort for studying the relative influence of endocrine and chromosomal factors. Here we compared serum levels of B-cell activating-factor (BAFF) and tumor necrosis factor (TNF) in transgender men (TM), transgender women (TW), cisgender women (CW) and cisgender men (CM)., Methods: BAFF and TNF were measured in the serum of 26 CW, 30 CM, 27 TM and 16 TW individuals. To determine the responsiveness of immune cells, TNF was measured in bacterial lipopolysaccharide (LPS)-treated peripheral leukocytes., Results: BAFF was higher in CF (998 pg/mL) and TW (973 pg/mL) compared to CM (551 pg/mL) (P < 0.0001) and TM (726 pg/mL) (P < 0.0001). No difference in BAFF levels was shown between subjects grouped according to the number of X chromosomes. TNF was higher in CM (174 pg/mL) than TW (2.3 pg/mL) (P = 0.027) and TM (27.4 pg/mL) (P = 0.028). LPS-induced TNF was higher in CM (2524 pg/mL) and TM (2078 pg/mL) than in CW (1332 pg/mL) (both P < 0.0001) and TW (1602 pg/mL) (both P = 0.009)., Discussion: Sex hormones and sex chromosomes have different impacts on cytokines involved in the sex-dependent inflammatory response. The concentration of BAFF and LPS-stimulated TNF secretion depended on sex hormone levels, whereas basal TNF was regulated by both sex hormone-dependent and -independent factors.

The impact of syndromic molecular diagnosis in the management of nosocomial infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens has been incompletely characterized. We evaluated the performance of a molecular syndromic platform (BioFire FilmArray-Pneumonia plus Panel) in patients with pneumonia in the intensive care unit (ICU) of a University Hospital in Greece over a 2-year period. We evaluated 79 consecutive patients diagnosed with pneumonia in the ICU (2018-2020), including 55 patients with ventilator associated pneumonia (VAP). We included 40 control patients diagnosed with pneumonia in the ICU the year before the study (2017-2018). We identified 16 cases of VAP due to XDR bacterial pathogens. We found an excellent agreement (89.4% 76/85 reported results) between the results of syndromic platform and conventional cultures of tracheal aspirates. The molecular syndromic test significantly improved time to diagnosis versus conventional culture (3.5 h vs 72 h, P <  0.0001), and identified new pathogens not detected by cultures in 49% of the cases. However, three cases of pneumonia with targets not included in the molecular platform, were not detected. Implementation of the molecular syndromic facilitated treatment modification from broad to narrow spectrum antimicrobial therapy, resulting in significant reductions in antibiotic consumption in the study group compared to the control group, without a negative impact in patient outcome. The implementation of syndromic molecular diagnosis in critically ill patients with pneumonia is associated with timely and improved diagnosis and has significant impact on reduction of antibiotic consumption. IMPORTANCE The impact of syndromic molecular diagnosis in the management of nosocomial infections caused by MDR/XDR pathogens has been incompletely characterized. We evaluated the performance of a molecular syndromic platform (BioFire FilmArray -Pneumonia plus Panel) in 79 patients with pneumonia in the intensive care unit (ICU) of a University Hospital in Greece over a 2-year period (2018-2020) compared to 40 control patients diagnosed with pneumonia in the ICU the year before the study (2017-2018). Importantly, implementation of syndromic pneumonia panel improved time to diagnosis, identified new pathogens not detected by cultures in 49% of the cases and resulted in a significant reduction in antibiotic consumption compared to the year before initiation of the study without a negative impact in mortality of patients. Collectively, our study demonstrates the positive value of PCR syndromic testing in the management of pneumonia in ICUs high rates of MDR/XDR nosocomial pathogens.

Background: Before the pandemic of coronavirus disease (COVID-19), rapidly improving acute respiratory distress syndrome (ARDS), mostly defined by early extubation, had been recognized as an increasingly prevalent subphenotype (making up 15-24% of all ARDS cases), associated with good prognosis (10% mortality in ARDSNet trials). We attempted to determine the prevalence and prognosis of rapidly improving ARDS and of persistent severe ARDS related to COVID-19., Methods: We included consecutive patients with COVID-19 receiving invasive mechanical ventilation in three intensive care units (ICU) during the second pandemic wave in Greece. We defined rapidly improving ARDS as extubation or a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO 2 :FiO 2 ) greater than 300 on the first day following intubation. We defined persistent severe ARDS as PaO 2 :FiO 2  of equal to or less than 100 on the second day following intubation., Results: A total of 280 intubated patients met criteria of ARDS with a median PaO 2 :FiO 2  of 125.0 (interquartile range 93.0-161.0) on day of intubation, and overall ICU-mortality of 52.5% (ranging from 24.3 to 66.9% across the three participating sites). Prevalence of rapidly improving ARDS was 3.9% (11 of 280 patients); no extubation occurred on the first day following intubation. ICU-mortality of patients with rapidly improving ARDS was 54.5%. This low prevalence and high mortality rate of rapidly improving ARDS were consistent across participating sites. Prevalence of persistent severe ARDS was 12.1% and corresponding mortality was 82.4%., Conclusions: Rapidly improving ARDS was not prevalent and was not associated with good prognosis among patients with COVID-19. This is starkly different from what has been previously reported for patients with ARDS not related to COVID-19. Our results on both rapidly improving ARDS and persistent severe ARDS may contribute to our understanding of trajectory of ARDS and its association with prognosis in patients with COVID-19., (© 2022. The Author(s).)

Introduction: : To adhere to the Hippocratic Oath, to 'first, do no harm', we need to make every effort to minimize the adverse effects of mechanical ventilation. Our understanding of the mechanisms of ventilator-induced lung injury (VILI) and ventilator-induced diaphragm dysfunction (VIDD) has increased in recent years. Research focuses now on methods to monitor lung stress and inhomogeneity and targets we should aim for when setting the ventilator. In parallel, efforts to promote early assisted ventilation to prevent VIDD have revealed new challenges, such as titrating inspiratory effort and synchronizing the mechanical with the patients' spontaneous breaths, while at the same time adhering to lung-protective targets., Areas Covered: This is a narrative review of the key mechanisms contributing to VILI and VIDD and the methods currently available to evaluate and mitigate the risk of lung and diaphragm injury., Expert Opinion: Implementing lung and diaphragm protective ventilation requires individualizing the ventilator settings, and this can only be accomplished by exploiting in everyday clinical practice the tools available to monitor lung stress and inhomogeneity, inspiratory effort, and patient-ventilator interaction.

Dyspnea on exertion is a devastating symptom, commonly observed in patients with pulmonary hypertension (PH). The pathophysiology of dyspnea in these patients has been mainly attributed to cardiovascular determinants and isolated abnormalities of the respiratory system during exercise, neglecting the contribution of the control of the breathing system. The aim of this review is to provide a novel approach to the interpretation of dyspnea in patients with PH, focused on the impact of the control of the breathing system during exercise. Exercise through multiple mechanisms affects the (1) ventilatory demands, as dictated by respiratory center activity, (2) actual ventilation, and (3) metabolic hyperbola. In patients with PH, exertional dyspnea can be explained by exercise-induced alterations in these variables. Compared to healthy subjects, at a given CO 2 production during exercise, ventilatory demands in patients with PH are higher due to metabolic acidosis (early reaching the anaerobic threshold), hypoxemia, and excessive upward movement of metabolic hyperbola owing to abnormal exercise response of dead space to tidal volume ratio. Simultaneously, dynamic hyperinflation and respiratory muscles weakness decreases the actual ventilation for a given respiratory center activity, creating a dissociation between demands and ventilation. Consequently, a progressive increase in ventilatory demands and respiratory center activity occurs during exercise. The forebrain projection of high respiratory center activity causes exertional dyspnea despite the relatively low ventilation and significant ventilatory reserve. This type of analysis suggests that the respiratory system is the main determinant of exertional dyspnea in patients with PH, with the cardiovascular system being an indirect contributor., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: The ventilatory ratio (VR) is a simple index of ventilatory efficiency and dead space. Because increased dead space and high ventilatory demands impose a limitation to unassisted ventilation, and may predispose patients to injurious strong efforts during assisted ventilation, evaluation of the VR could provide helpful information during weaning. We hypothesize that there is a threshold of VR associated with tolerance of unassisted breathing., Methods: In a retrospective analysis, we included subjects ventilated in a control mode for at least 24 h, who were successfully liberated from mechanical ventilation, without use of noninvasive ventilation, and discharged alive from the ICU. We focused on the successful weaning attempts (the last, if more than one was performed) and evaluated the VR at the beginning and at the end of the assisted ventilation period., Results: We examined 2,000 medical records and included in our analysis 572 subjects (age: 68 y, R 5-95 = 25-85, 68% male) with main admission diagnosis of respiratory failure (23%), sepsis (11%), brain injury (34%), and postoperative (14%). The VR at the beginning and the end of the assisted ventilation period was 1.5 (R 5-95 = 1-2.1) and 1.4 (R 5-95 = 1-2), respectively. The median duration of assisted ventilation in subjects with a VR ≥ 2 at the beginning of the assisted ventilation period was 3 d (R 5-95 = 0-14 d), significantly longer than in those with a VR < 2, 0.5 d (R 5-95 = 0-8 d, P < .001)., Conclusions: Successful liberation from assisted ventilation was associated with a VR < 2. A VR > 2 was associated with longer duration of weaning. The VR could be used as an additional tool to facilitate the decision-making process during weaning., Competing Interests: Drs Georgopoulos, Kondili, and Vaporidi disclose relationships with Medtronic. The other authors have no conflicts to disclose., (Copyright © 2021 by Daedalus Enterprises.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3 + phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To describe the correlation between the inspiratory esophageal and transdiaphragmatic pressure swings (ΔPes and ΔPdi), easily measured indices of inspiratory effort, with the gold-standard, the transdiaphragmatic pressure time product (PTP Pdi /min), and assess the accuracy of swing pressures in predicting very high or low effort., Method: Retrospective analysis of data from patients enrolled in four previous studies. ROC curves of ΔPes and ΔPdi values for specific PTP Pdi /min thresholds (50, 150, 200 cmH 2 O × sec/min) were constructed, and the diagnostic accuracy of different thresholds of swing values were computed., Results: A threshold of inspiratory ΔP<7cmH 2 O can be used to identify most patients with low effort, as lower ΔP thresholds have low sensitivity. Thresholds of inspiratory ΔP>14-18cmH 2 O can be used to identify patients with very high inspiratory effort (PTP Pdi /min> 200 cmH 2 O × sec/min)., Conclusions: The results of this study can help clinicians better select and interpret thresholds of ΔP to evaluate inspiratory effort., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Mechanical ventilation services are an important driver of the high costs of intensive care. An optimal interaction between a patient and a ventilator is therefore paramount. Suboptimal interaction is present when patients repeatedly demand, but do not receive, breathing support from a mechanical ventilator (> 30 times in 3 min), also known as an ineffective effort event (IEEV). IEEVs are associated with increased hospital mortality prolonged intensive care stay, and prolonged time on ventilation and thus development of real-time analytics that identify IEEVs is essential. To assist decision-making about further development we estimate the potential cost-effectiveness of real-time analytics that identify ineffective effort events., Methods: We developed a cost-effectiveness model combining a decision tree and Markov model for long-term outcomes with data on current care from a Greek hospital and literature. A lifetime horizon and a healthcare payer perspective were used. Uncertainty about the results was assessed using sensitivity and scenario analyses to examine the impact of varying parameters like the intensive care costs per day and the effectiveness of treatment of IEEVs., Results: Use of the analytics could lead to reduced mortality (3% absolute reduction), increased quality adjusted life years (0.21 per patient) and cost-savings (€264 per patient) compared to current care. Moreover, cost-savings for hospitals and health improvements can be incurred even if the treatment's effectiveness is reduced from 30 to 10%. The estimated savings increase to €1,155 per patient in countries where costs of an intensive care day are high (e.g. the Netherlands). There is considerable headroom for development and the analytics generate savings when the price of the analytics per bed per year is below €7,307. Furthermore, even when the treatment's effectiveness is 10%, the probability that the analytics are cost-effective exceeds 90%., Conclusions: Implementing real-time analytics to identify ineffective effort events can lead to health and financial benefits. Therefore, it will be worthwhile to continue assessment of the effectiveness of the analytics in clinical practice and validate our findings. Eventually, their adoption in settings where costs of an intensive care day are high and ineffective efforts are frequent could yield a high return on investment.

Mechanical ventilation may have adverse effects on both the lung and the diaphragm. Injury to the lung is mediated by excessive mechanical stress and strain, whereas the diaphragm develops atrophy as a consequence of low respiratory effort and injury in case of excessive effort. The lung and diaphragm-protective mechanical ventilation approach aims to protect both organs simultaneously whenever possible. This review summarizes practical strategies for achieving lung and diaphragm-protective targets at the bedside, focusing on inspiratory and expiratory ventilator settings, monitoring of inspiratory effort or respiratory drive, management of dyssynchrony, and sedation considerations. A number of potential future adjunctive strategies including extracorporeal CO 2 removal, partial neuromuscular blockade, and neuromuscular stimulation are also discussed. While clinical trials to confirm the benefit of these approaches are awaited, clinicians should become familiar with assessing and managing patients' respiratory effort, based on existing physiological principles. To protect the lung and the diaphragm, ventilation and sedation might be applied to avoid excessively weak or very strong respiratory efforts and patient-ventilator dysynchrony.

Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient-ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.

Aim: To describe the response of breathing pattern and inspiratory effort upon changes in assist level and to assesss if changes in respiratory rate may indicate changes in respiratory muscle effort., Methods: Prospective study of 82 patients ventilated on proportional assist ventilation (PAV+). At three levels of assist (20 %-50 %-80 %), patients' inspiratory effort and breathing pattern were evaluated using a validated prototype monitor., Results: Independent of the assist level, a wide range of respiratory rates (16-35br/min) was observed when patients' effort was within the accepted range. Changing the assist level resulted in paired changes in inspiratory effort and rate of the same tendency (increase or decrease) in all but four patients. Increasing the level in assist resulted in a 31 % (8-44 %) decrease in inspiratory effort and a 10 % (0-18 %) decrease in respiratory rate. The change in respiratory rate upon the change in assist correlated modestly with the change in the effort (R = 0.5)., Conclusion: Changing assist level results in changes in both respiratory rate and effort in the same direction, with change in effort being greater than that of respiratory rate. Yet, neither the magnitude of respiratory rate change nor the resulting absolute value may reliably predict the level of effort after a change in assist., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The driving pressure of the respiratory system is a valuable indicator of global lung stress during passive mechanical ventilation. Monitoring lung stress in assisted ventilation is indispensable, but achieving passive conditions in spontaneously breathing patients to measure driving pressure is challenging. The accuracy of the morphology of airway pressure (Paw) during end-inspiratory occlusion to assure passive conditions during pressure support ventilation has not been examined., Methods: Retrospective analysis of end-inspiratory occlusions obtained from critically ill patients during pressure support ventilation. Flow, airway, esophageal, gastric, and transdiaphragmatic pressures were analyzed. The rise of gastric pressure during occlusion with a constant/decreasing transdiaphragmatic pressure was used to identify and quantify the expiratory muscle activity. The Paw during occlusion was classified in three patterns, based on the differences at three pre-defined points after occlusion (0.3, 1, and 2 s): a "passive-like" decrease followed by plateau, a pattern with "clear plateau," and an "irregular rise" pattern, which included all cases of late or continuous increase, with or without plateau., Results: Data from 40 patients and 227 occlusions were analyzed. Expiratory muscle activity during occlusion was identified in 79% of occlusions, and at all levels of assist. After classifying occlusions according to Paw pattern, expiratory muscle activity was identified in 52%, 67%, and 100% of cases of Paw of passive-like, clear plateau, or irregular rise pattern, respectively. The driving pressure was evaluated in the 133 occlusions having a passive-like or clear plateau pattern in Paw. An increase in gastric pressure was present in 46%, 62%, and 64% of cases at 0.3, 1, and 2 s, respectively, and it was greater than 2 cmH 2 O, in 10%, 20%, and 15% of cases at 0.3, 1, and 2 s, respectively., Conclusions: The pattern of Paw during an end-inspiratory occlusion in pressure support cannot assure the absence of expiratory muscle activity and accurate measurement of driving pressure. Yet, because driving pressure can only be overestimated due to expiratory muscle contraction, in everyday practice, a low driving pressure indicates an absence of global lung over-stretch. A measurement of high driving pressure should prompt further diagnostic workup, such as a measurement of esophageal pressure.

Purpose of Review: Complications of mechanical ventilation, such as ventilator-induced lung injury (VILI) and ventilator-induced diaphragmatic dysfunction (VIDD), adversely affect the outcome of critically ill patients. Although mostly studied during control ventilation, it is increasingly appreciated that VILI and VIDD also occur during assisted ventilation. Hence, current research focuses on identifying ways to monitor and deliver protective ventilation in assisted modes. This review describes the operating principles of proportional modes of assist, their implications for lung and diaphragm protective ventilation, and the supporting clinical data., Recent Findings: Proportional modes of assist, proportional assist ventilation, PAV, and neurally adjusted ventilatory assist, NAVA, deliver a pressure assist that is proportional to the patient's effort, enabling ventilation to be better controlled by the patient's brain. This control underlies the potential of proportional modes to avoid over-assist and under-assist, improve patient--ventilator interaction, and provide protective ventilation. Indeed, in clinical studies, proportional modes have been associated with reduced asynchronies, enhanced diaphragmatic recovery, and limitation of excessive tidal volume. Additionally, proportional modes facilitate better monitoring of the delivery of protective assisted ventilation., Summary: Physiological rationale and clinical data suggest a potential role for proportional modes of assist in providing and monitoring lung and diaphragm protective ventilation.

Respiratory drive, the intensity of the respiratory center's output, determines the effort exerted in each breath. The increasing awareness of the adverse effects of both strong and weak respiratory efforts during mechanical ventilation on patient outcome brings attention to the respiratory drive of the critically ill patient. Critical illness can affect patients' respiratory drive through multiple pathways, mainly operating through three feedback systems: cortical, metabolic, and chemical. The chemical feedback system, defined as the response of the respiratory center's output to changes in arterial blood gases and pH, is one of the most important determinants of respiratory drive. The purpose of this state-of-the-art review is to describe the determinants of respiratory drive in critically ill patients, review the tools available to assess respiratory drive at the bedside, and discuss the implications of altered respiratory drive during mechanical ventilation. An analysis that relates arterial carbon dioxide levels with brain's response to this stimulus will be presented, contrasting the brain's responses to the patient's ability to generate effective alveolar ventilation, both during unassisted breathing and with different modes of ventilatory assist. This analysis may facilitate comprehension of the pathophysiology of respiratory drive in critically ill patients. As we aim to avoid both over- and under-assistance with mechanical ventilation, considering the patients' respiratory drive at the bedside may improve clinical assessment and management of the patient and the ventilator.