Driving pressure of respiratory system and lung stress in mechanically ventilated patients with active breathing.

BACKGROUND: During control mechanical ventilation (CMV), the driving pressure of the respiratory system (ΔPrs) serves as a surrogate of transpulmonary driving pressure (ΔPlung). Expiratory muscle activity that decreases end-expiratory lung volume may impair the validity of ΔPrs to reflect ΔPlung. 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 ΔPlung, (2) the ΔPrs-ΔPlung relationship, and (3) whether dynamic transpulmonary pressure (Plungsw) 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 (Elung). Patients were divided into Group A, if end-inspiratory transpulmonary pressure (PLEI) increased as Elung increased, and Group B, which showed a decrease or no change in PLEI with Elung increase. RESULTS: In 44,836 occluded breaths, ΔPlung ≥ 12 cmH2O 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 ΔPlung by ΔPrs, as suggested by a negative linear relationship between transpulmonary pressure at end-expiration (PLEE) and ΔPlung/ΔPrs. Group A included 17 and Group B 14 patients. As Elung increased, ΔPlung increased mainly due to PLEI increase in Group A, and PLEE decrease in Group B. Although ΔPrs had an area receiver operating characteristic curve (AUC) of 0.87 (95% confidence intervals 0.82-0.92, P < 0.001) for ΔPlung ≥ 12 cmH2O, this was due exclusively to Group A [0.91 (0.86-0.95), P < 0.001]. In Group B, ΔPrs showed no predictive capacity for detecting ΔPlung ≥ 12 cmH2O [0.65 (0.52-0.78), P > 0.05]. Most of the time Plungsw 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, ΔPrs underestimated ΔPlung. This phenomenon limits the usefulness of ΔPrs as a surrogate of tidal lung stress, regardless of the mode of support.

Performance of Lung Ultrasound for Monitoring Interstitial Lung Disease.

OBJECTIVES: In this study, we sought to assess the validity of lung ultrasound (LUS) during the follow-up of patients with a wide spectrum of interstitial lung diseases (ILDs). METHODS: Twenty-four patients (13 males, 11 females; mean age ± SD, 65.4 ± 14.3 years; age range, 40-84 years) with a diagnosis of ILDs who were admitted to the Interstitial Lung Disease Unit were prospectively enrolled. Patients were examined with a 56-lung intercostal space LUS protocol in lateral decubitus position, at baseline, 6-months, and 1-year. The LUS score was defined as the sum of B-lines counted in each intercostal space. All patients underwent complete pulmonary function tests at baseline and follow-up time-points. High-resolution computed tomography (HRCT) was performed at baseline and during follow-up, according to personalized patients' needs. All HRCT studies were graded according to the Warrick scoring system (WS). RESULTS: Pooled data analysis showed a significant correlation between WS and LUS scores (P < .001). For separate time-point analysis, a significant correlation between LUS scores and WS was found at baseline (P < .001) and 1 year (P = .005). LUS scores negatively correlated with alveolar volume (VA) (P < .046) and diffusing capacity for carbon monoxide (DLCO) (P < .001) at 6 months and with transfer coefficient of the lung for carbon monoxide (KCO) (P < .031) and DLCO (P = .002) at 12-months. A multivariate regression model showed DLCO to be an independent predictor of LUS score at 1 year (P = .026). CONCLUSIONS: Our results highlight the validity and potential applicability of LUS for disease monitoring in a wide spectrum of ILDs.

Lung- and Diaphragm-Protective Ventilation.

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.

A physiology-based mathematical model for the selection of appropriate ventilator controls for lung and diaphragm protection.

Mechanical ventilation is used to sustain respiratory function in patients with acute respiratory failure. To aid clinicians in consistently selecting lung- and diaphragm-protective ventilation settings, a physiology-based decision support system is needed. To form the foundation of such a system, a comprehensive physiological model which captures the dynamics of ventilation has been developed. The Lung and Diaphragm Protective Ventilation (LDPV) model centers around respiratory drive and incorporates respiratory system mechanics, ventilator mechanics, and blood acid-base balance. The model uses patient-specific parameters as inputs and outputs predictions of a patient's transpulmonary and esophageal driving pressures (outputs most clinically relevant to lung and diaphragm safety), as well as their blood pH, under various ventilator and sedation conditions. Model simulations and global optimization techniques were used to evaluate and characterize the model. The LDPV model is demonstrated to describe a CO2 respiratory response that is comparable to what is found in literature. Sensitivity analysis of the model indicate that the ventilator and sedation settings incorporated in the model have a significant impact on the target output parameters. Finally, the model is seen to be able to provide robust predictions of esophageal pressure, transpulmonary pressure and blood pH for patient parameters with realistic variability. The LDPV model is a robust physiological model which produces outputs which directly target and reflect the risk of ventilator-induced lung and diaphragm injury. Ventilation and sedation parameters are seen to modulate the model outputs in accordance with what is currently known in literature.

Akt2 deficiency protects from acute lung injury via alternative macrophage activation and miR-146a induction in mice.

Acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure, with limited effective treatments available. Alveolar macrophages participate in the pathogenesis of ARDS. To investigate the role of macrophage activation in aseptic lung injury and identify molecular mediators with therapeutic potential, lung injury was induced in wild-type (WT) and Akt2(-/-) mice by hydrochloric acid aspiration. Acid-induced lung injury in WT mice was characterized by decreased lung compliance and increased protein and cytokine concentration in bronchoalveolar lavage fluid. Alveolar macrophages acquired a classical activation (M1) phenotype. Acid-induced lung injury was less severe in Akt2(-/-) mice compared with WT mice. Alveolar macrophages from acid-injured Akt2(-/-) mice demonstrated the alternative activation phenotype (M2). Although M2 polarization suppressed aseptic lung injury, it resulted in increased lung bacterial load when Akt2(-/-) mice were infected with Pseudomonas aeruginosa. miR-146a, an anti-inflammatory microRNA targeting TLR4 signaling, was induced during the late phase of lung injury in WT mice, whereas it was increased early in Akt2(-/-) mice. Indeed, miR-146a overexpression in WT macrophages suppressed LPS-induced inducible NO synthase (iNOS) and promoted M2 polarization, whereas miR-146a inhibition in Akt2(-/-) macrophages restored iNOS expression. Furthermore, miR-146a delivery or Akt2 silencing in WT mice exposed to acid resulted in suppression of iNOS in alveolar macrophages. In conclusion, Akt2 suppression and miR-146a induction promote the M2 macrophage phenotype, resulting in amelioration of acid-induced lung injury. In vivo modulation of macrophage phenotype through Akt2 or miR-146a could provide a potential therapeutic approach for aseptic ARDS; however, it may be deleterious in septic ARDS because of impaired bacterial clearance.

Respiratory drive: a journey from health to disease.

Respiratory drive is defined as the intensity of respiratory centers output during the breath and is primarily affected by cortical and chemical feedback mechanisms. During the involuntary act of breathing, chemical feedback, primarily mediated through CO2, is the main determinant of respiratory drive. Respiratory drive travels through neural pathways to respiratory muscles, which execute the breathing process and generate inspiratory flow (inspiratory flow-generation pathway). In a healthy state, inspiratory flow-generation pathway is intact, and thus respiratory drive is satisfied by the rate of volume increase, expressed by mean inspiratory flow, which in turn determines tidal volume. In this review, we will explain the pathophysiology of altered respiratory drive by analyzing the respiratory centers response to arterial partial pressure of CO2 (PaCO2) changes. Both high and low respiratory drive have been associated with several adverse effects in critically ill patients. Hence, it is crucial to understand what alters the respiratory drive. Changes in respiratory drive can be explained by simultaneously considering the (1) ventilatory demands, as dictated by respiratory centers activity to CO2 (brain curve); (2) actual ventilatory response to CO2 (ventilation curve); and (3) metabolic hyperbola. During critical illness, multiple mechanisms affect the brain and ventilation curves, as well as metabolic hyperbola, leading to considerable alterations in respiratory drive. In critically ill patients the inspiratory flow-generation pathway is invariably compromised at various levels. Consequently, mean inspiratory flow and tidal volume do not correspond to respiratory drive, and at a given PaCO2, the actual ventilation is less than ventilatory demands, creating a dissociation between brain and ventilation curves. Since the metabolic hyperbola is one of the two variables that determine PaCO2 (the other being the ventilation curve), its upward or downward movements increase or decrease respiratory drive, respectively. Mechanical ventilation indirectly influences respiratory drive by modifying PaCO2 levels through alterations in various parameters of the ventilation curve and metabolic hyperbola. Understanding the diverse factors that modulate respiratory drive at the bedside could enhance clinical assessment and the management of both the patient and the ventilator.

Lung- and diaphragm-protective strategies in acute respiratory failure: an in silico trial.

BACKGROUND: Lung- and diaphragm-protective (LDP) ventilation may prevent diaphragm atrophy and patient self-inflicted lung injury in acute respiratory failure, but feasibility is uncertain. The objectives of this study were to estimate the proportion of patients achieving LDP targets in different modes of ventilation, and to identify predictors of need for extracorporeal carbon dioxide removal (ECCO2R) to achieve LDP targets. METHODS: An in silico clinical trial was conducted using a previously published mathematical model of patient-ventilator interaction in a simulated patient population (n = 5000) with clinically relevant physiological characteristics. Ventilation and sedation were titrated according to a pre-defined algorithm in pressure support ventilation (PSV) and proportional assist ventilation (PAV+) modes, with or without adjunctive ECCO2R, and using ECCO2R alone (without ventilation or sedation). Random forest modelling was employed to identify patient-level factors associated with achieving targets. RESULTS: After titration, the proportion of patients achieving targets was lower in PAV+ vs. PSV (37% vs. 43%, odds ratio 0.78, 95% CI 0.73-0.85). Adjunctive ECCO2R substantially increased the probability of achieving targets in both PSV and PAV+ (85% vs. 84%). ECCO2R alone without ventilation or sedation achieved LDP targets in 9%. The main determinants of success without ECCO2R were lung compliance, ventilatory ratio, and strong ion difference. In silico trial results corresponded closely with the results obtained in a clinical trial of the LDP titration algorithm (n = 30). CONCLUSIONS: In this in silico trial, many patients required ECCO2R in combination with mechanical ventilation and sedation to achieve LDP targets. ECCO2R increased the probability of achieving LDP targets in patients with intermediate degrees of derangement in elastance and ventilatory ratio.

Neural Network-Enabled Identification of Weak Inspiratory Efforts during Pressure Support Ventilation Using Ventilator Waveforms.

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 cmH2O*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.

Hiccup-like Contractions in Mechanically Ventilated Patients: Individualized Treatment Guided by Transpulmonary Pressure.

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.

Evaluation of the Acid-Base Status in Patients Admitted to the ICU Due to Severe COVID-19: Physicochemical versus Traditional Approaches.

BACKGROUND: Stewart's approach is known to have better diagnostic accuracy for the identification of metabolic acid-base disturbances compared to traditional methods based either on plasma bicarbonate concentration ([HCO3-]) and anion gap (AG) or on base excess/deficit (BE). This study aimed to identify metabolic acid-base disorders using either Stewart's or traditional approaches in critically ill COVID-19 patients admitted to the ICU, to recognize potential hidden acid-base metabolic abnormalities and to assess the prognostic value of these abnormalities for patient outcome. METHODS: This was a single-center retrospective study, in which we collected data from patients with severe COVID-19 admitted to the ICU. Electronical files were used to retrieve data for arterial blood gases, serum electrolytes, and proteins and to derive [HCO3-], BE, anion gap (AG), AG adjusted for albumin (AGadj), strong ion difference, strong ion gap (SIG), and SIG corrected for water excess/deficit (SIGcorr). The acid-base status was evaluated in each patient using the BE, [HCO3-], and physicochemical approaches. RESULTS: We included 185 patients. The physicochemical approach detected more individuals with metabolic acid-base abnormalities than the BE and [HCO3-] approaches (p < 0.001), and at least one acid-base disorder was recognized in most patients. According to the physicochemical method, 170/185 patients (91.4%) had at least one disorder, as opposed to the number of patients identified using the BE 90/186 (48%) and HCO3 62/186 (33%) methods. Regarding the derived acid-base status variables, non-survivors had greater AGadj, (p = 0.013) and SIGcorr (p = 0.035) compared to survivors. CONCLUSIONS: The identification of hidden acid-base disturbances may provide a detailed understanding of the underlying conditions in patients and of the possible pathophysiological mechanisms implicated. The association of these acid-base abnormalities with mortality provides the opportunity to recognize patients at increased risk of death and support them accordingly.

Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury.

The aim of this study was to investigate the changes induced by high tidal volume ventilation (HVTV) in pulmonary expression of micro-RNAs (miRNAs) and identify potential target genes and corresponding miRNA-gene networks. Using a real-time RT-PCR-based array in RNA samples from lungs of mice subjected to HVTV for 1 or 4 h and control mice, we identified 65 miRNAs whose expression changed more than twofold upon HVTV. An inflammatory and a TGF-ß-signaling miRNA-gene network were identified by in silico pathway analysis being at highest statistical significance (P = 10(-43) and P = 10(-28), respectively). In the inflammatory network, IL-6 and SOCS-1, regulated by miRNAs let-7 and miR-155, respectively, appeared as central nodes. In TGF-ß-signaling network, SMAD-4, regulated by miR-146, appeared as a central node. The contribution of miRNAs to the development of lung injury was evaluated in mice subjected to HVTV treated with a precursor or antagonist of miR-21, a miRNA highly upregulated by HVTV. Lung compliance was preserved only in mice treated with anti-miR-21 but not in mice treated with pre-miR-21 or negative-control miRNA. Both alveolar-arterial oxygen difference and protein levels in bronchoalveolar lavage were lower in mice treated with anti-miR-21 than in mice treated with pre-miR-21 or negative-control miRNA (D(A-a): 66 ± 27 vs. 131 ± 22, 144 ± 10 mmHg, respectively, P < 0.001; protein concentration: 1.1 ± 0.2 vs. 2.3 ± 1, 2.1 ± 0.4 mg/ml, respectively, P < 0.01). Our results show that HVTV induces changes in miRNA expression in mouse lungs. Modulation of miRNA expression can affect the development of HVTV-induced lung injury.

Comparison of Oligon catheters and chlorhexidine-impregnated sponges with standard multilumen central venous catheters for prevention of associated colonization and infections in intensive care unit patients: a multicenter, randomized, controlled study.

OBJECTIVE: To evaluate silver-impregnated (Oligon) central venous catheters and chlorhexidine-gluconate-impregnated sponges for reducing catheter-related colonization and infection, nonbacteremic or bacteremic. DESIGN: Multicenter, prospective, randomized, controlled study. SETTING: Five general intensive care units in Greece. PATIENTS: Intensive care unit patients requiring a multilumen central venous catheter between June 2006 and May 2008. INTERVENTIONS: Patients were randomly assigned to receive a standard catheter (standard group), a standard catheter plus chlorhexidine-gluconate-impregnated sponge (chlorhexidine-gluconate-impregnated sponge group), or an Oligon catheter (Oligon group). Catheter colonization was defined as a positive quantitative tip culture (≥10 colony-forming units/mL), catheter-related infection was defined by the previous criterion plus clinical evidence of sepsis, and bacteremia catheter-related infection as catheter-related infection plus a positive peripheral blood culture with the same micro-organism as in the catheter tip. MEASUREMENTS AND MAIN RESULTS: Data were obtained from 465 patients, 156 in the standard-group, 150 in the chlorhexidine-gluconate-impregnated sponge group, and 159 in the Oligon-group. Colonization occurred in 24 (15.4%) standard catheters, 21 (14%) in the chlorhexidine-gluconate-impregnated sponge group, and 25 (15.7%) in the Oligon catheters (p = .35) (20.9, 19.9, 21.8/1000 catheter-days, respectively). Catheter-related infections were recorded in nine (5.8%) standard catheters, six (4%) in the chlorhexidine-gluconate-impregnated sponge group, and seven (4.4%) in the Oligon catheters (p = .58) (7.8/1,000, 5.7/1,000, 6.1/1,000 catheter-days, respectively). No difference was observed between the chlorhexidine- gluconate-impregnated sponge group and the standard group regarding catheter colonization (hazard ratio 1.21; 95% confidence interval 0.56-2.61; p = .64) and catheter-related infections (hazard ratio 0.65; 95% confidence interval 0.23-1.85; p = .42). The Oligon catheter did not reduce colonization or catheter-related infections when compared with the standard catheter (colonization: hazard ratio 1.0; 95% confidence interval 0.46-2.21; p = .98; catheter-related infection: hazard ratio 0.72; 95% confidence interval 0.27-1.95; p = .52). Seven patients (1.5%, 2.09/1,000 catheter-days) presented bacteremic catheter-related infections. Central venous catheters inserted either in the internal jugular or the femoral vein had greater risk to be colonized than catheters inserted in the subclavian vein (internal jugular vs. subclavian: hazard ratio 3.29; 95% confidence interval 1.26-8.61; p = .01; femoral vs. subclavian: hazard ratio 3.36; 95% confidence interval 1.17-9.65; p = .02). Acinetobacter baumannii was the predominant pathogen (37.1% episodes of colonization, 36.4% catheter-related infections, 57.1% bacteremic catheter-related infections). CONCLUSION: For short-term (median duration 7 days) central venous catheters in intensive care units with high prevalence of multiresistant Gram-negative bacteria, chlorhexidine-impregnated sponges and Oligon catheters as single preventive measures did not reduce catheter colonization or catheter-related infections. As a result of the limited amount of events, no conclusion could be reached regarding bacteremic catheter-related infections. The femoral site was the most frequently colonized insertion site in all types of catheters.

Defining the needs of ICU patient families in a suburban/rural Greek population: a prospective cohort study.

AIM: To define the needs of intensive care unit patients' families in the specific suburban/rural population of Crete Island. BACKGROUND: Families of intensive care unit patients have specific needs that should also be addressed by the intensive care unit-care team. Current research has mostly concentrated on families from an urban setting, therefore may not be applicable to other populations. DESIGN: Prospective cohort study. METHODS: Family members of patients admitted in the intensive care unit for ≥ 48 hours over 18 months, in a mixed medical-surgical, 11 bed closed intensive care unit. Questionnaire: The Greek translation of Critical Care Family Need Inventory, which consists of 45 need items covering the information, reassurance, proximity, support and comfort domains. Each item was scored on a four-point scale (1 = very important to 4 = not important). Participants were also asked to single out the most important need from the Critical Care Family Need Inventory and complete a questionnaire on basic demographic characteristics. RESULTS: Two hundred and thirty (65%) family members completed the questionnaire. Mean score for each of the 45 items ranged from 1.03-3 (scale from 1: very important-4: not important). Fourteen items were rated by responders as very important (mean score <1.25). Reassurance need items were consistently singled out as most important regardless of the participant's background. Participants with a lower educational and socio-economical status rated support need items as more important than those with a higher status. CONCLUSION: In this particular suburban/rural population, both 'universal' reassurance needs and specific support needs related to responders' educational or socio-economical background were identified. RELEVANCE TO CLINICAL PRACTICE: Enhanced recognition of these needs may improve quality of care offered by intensive care unit-care team to families of their patients.

Impact of Molecular Syndromic Diagnosis of Severe Pneumonia in the Management of Critically Ill Patients.

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.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

COVID-19 ARDS: Points to Be Considered in Mechanical Ventilation and Weaning.

The COVID-19 disease can cause hypoxemic respiratory failure due to ARDS, requiring invasive mechanical ventilation. Although early studies reported that COVID-19-associated ARDS has distinctive features from ARDS of other causes, recent observational studies have demonstrated that ARDS related to COVID-19 shares common clinical characteristics and respiratory system mechanics with ARDS of other origins. Therefore, mechanical ventilation in these patients should be based on strategies aiming to mitigate ventilator-induced lung injury. Assisted mechanical ventilation should be applied early in the course of mechanical ventilation by considering evaluation and minimizing factors associated with patient-inflicted lung injury. Extracorporeal membrane oxygenation should be considered in selected patients with refractory hypoxia not responding to conventional ventilation strategies. This review highlights the current and evolving practice in managing mechanically ventilated patients with ARDS related to COVID-19.

Ventilatory Ratio Threshold for Unassisted Breathing: A Retrospective Exploratory Analysis.

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, R5-95 = 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 (R5-95 = 1-2.1) and 1.4 (R5-95 = 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 (R5-95 = 0-14 d), significantly longer than in those with a VR < 2, 0.5 d (R5-95 = 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.

Survivin and caspases serum protein levels and survivin variants mRNA expression in sepsis.

Sepsis is a dysregulated host response to infection related to devastating outcomes. Recently, interest has been shifted towards apoptotic and antiapoptotic pathobiology. Apoptosis is executed through the activation of caspases regulated by a number of antiapoptotic proteins, such as survivin. The survivin and caspases' responses to sepsis have not yet been elucidated. This is a multicenter prospective observational study concerning patients with sepsis (n = 107) compared to patients with traumatic systemic inflammatory response syndrome (SIRS) (n = 75) and to healthy controls (n = 89). The expression of survivin was quantified through real-time quantitative polymerase chain reaction for the different survivin splice variants (wild type-WT, ΔEx3, 2B, 3B) in peripheral blood leukocytes. The apoptotic or antiapoptotic tendency was specified by measuring survivin-WT, caspase-3, and -9 serum protein concentrations through enzyme-linked immunosorbent assay. The survivin-WT, -2B, -ΔΕx3 mRNA, survivin protein, and caspases showed an escalated increase in SIRS and sepsis, whereas survivin-3B was repressed in sepsis (p < 0.05). Survivin correlated with IL-8 and caspase-9 (p < 0.01). For discriminating sepsis, caspase-9 achieved the best receiver operating characteristic curve (AUROC) of 0.95. In predicting mortality, caspase-9 and survivin protein achieved an AUROC of 0.70. In conclusion, specific apoptotic and antiapoptotic pathways might represent attractive targets for future research in sepsis.

Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis.

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.