Design and Rationale of the Sevoflurane for Sedation in Acute Respiratory Distress Syndrome (SESAR) Randomized Controlled Trial.

Preclinical studies have shown that volatile anesthetics may have beneficial effects on injured lungs, and pilot clinical data support improved arterial oxygenation, attenuated inflammation, and decreased lung epithelial injury in patients with acute respiratory distress syndrome (ARDS) receiving inhaled sevoflurane compared to intravenous midazolam. Whether sevoflurane is effective in improving clinical outcomes among patients with ARDS is unknown, and the benefits and risks of inhaled sedation in ARDS require further evaluation. Here, we describe the SESAR (Sevoflurane for Sedation in ARDS) trial designed to address this question. SESAR is a two-arm, investigator-initiated, multicenter, prospective, randomized, stratified, parallel-group clinical trial with blinded outcome assessment designed to test the efficacy of sedation with sevoflurane compared to intravenous propofol in patients with moderate to severe ARDS. The primary outcome is the number of days alive and off the ventilator at 28 days, considering death as a competing event, and the key secondary outcome is 90 day survival. The planned enrollment is 700 adult participants at 37 French academic and non-academic centers. Safety and long-term outcomes will be evaluated, and biomarker measurements will help better understand mechanisms of action. The trial is funded by the French Ministry of Health, the European Society of Anaesthesiology, and Sedana Medical.

Changes in Plasma Soluble Receptor for Advanced Glycation End-Products Are Associated with Survival in Patients with Acute Respiratory Distress Syndrome.

The plasma soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury with prognostic value when measured at baseline in acute respiratory distress syndrome (ARDS). However, whether changes in plasma sRAGE could inform prognosis in ARDS remains unknown. In this secondary analysis of the Lung Imaging for Ventilator Setting in ARDS (LIVE) multicenter randomized controlled trial, which evaluated a personalized ventilation strategy tailored to lung morphology, plasma sRAGE was measured upon study entry (baseline) and on days one, two, three, four and six. The association between changes in plasma sRAGE over time and 90-day survival was evaluated. Higher baseline plasma sRAGE (HR per-one log increment, 1.53; 95% CI, 1.16-2.03; p = 0.003) and an increase in sRAGE over time (HR for each one-log increment in plasma sRAGE per time unit, 1.01; 95% CI, 1.01-1.02; p < 10-3) were both associated with increased 90-day mortality. Each 100-unit increase in the plasma sRAGE level per unit of time increased the risk of death at day 90 by 1% in joint modeling. Plasma sRAGE increased over time when a strategy of maximal alveolar recruitment was applied in patients with focal ARDS. Current findings suggest that the rate of change in plasma sRAGE over time is associated with 90-day survival and could be helpful as a surrogate outcome in ARDS.

Use of volatile agents for sedation in the intensive care unit: A national survey in France.

BACKGROUND: Current intensive care unit (ICU) sedation guidelines recommend strategies using non-benzodiazepine sedatives. This survey was undertaken to explore inhaled ICU sedation practice in France. METHODS: In this national survey, medical directors of French adult ICUs were contacted by phone or email between July and August 2019. ICU medical directors were questioned about the characteristics of their department, their knowledge on inhaled sedation, and practical aspects of inhaled sedation use in their department. RESULTS: Among the 374 ICUs contacted, 187 provided responses (50%). Most ICU directors (73%) knew about the use of inhaled ICU sedation and 21% used inhaled sedation in their unit, mostly with the Anaesthetic Conserving Device (AnaConDa, Sedana Medical). Most respondents had used volatile agents for sedation for <5 years (63%) and in <20 patients per year (75%), with their main indications being: failure of intravenous sedation, severe asthma or bronchial obstruction, and acute respiratory distress syndrome. Sevoflurane and isoflurane were mainly used (88% and 20%, respectively). The main reasons for not using inhaled ICU sedation were: "device not available" (40%), "lack of medical interest" (37%), "lack of familiarity or knowledge about the technique" (35%) and "elevated cost" (21%). Most respondents (80%) were overall satisfied with the use of inhaled sedation. Almost 75% stated that inhaled sedation was a seducing alternative to intravenous sedation. CONCLUSION: This survey highlights the widespread knowledge about inhaled ICU sedation in France but shows its limited use to date. Differences in education and knowledge, as well as the recent and relatively scarce literature on the use of volatile agents in the ICU, might explain the diverse practices that were observed. The low rate of mild adverse effects, as perceived by respondents, and the users' satisfaction, are promising for this potentially important tool for ICU sedation.

Blunt Chest Trauma and Regional Anesthesia for Analgesia of Multitrauma Patients in French Intensive Care Units: A National Survey.

BACKGROUND: Chest injuries are associated with mortality among patients admitted to the intensive care unit (ICU) and require multimodal pain management strategies, including regional anesthesia (RA). We conducted a survey to determine the current practices of physicians working in ICUs regarding RA for the management of chest trauma in patients with multiple traumas. METHODS: An online questionnaire was sent to medical doctors (n = 1230) working in French ICUs, using the Société Française d'Anesthésie Réanimation (SFAR) mailing list of its members. The questionnaire addressed 3 categories: general characteristics, practical aspects of RA, and indications and contraindications. RESULTS: Among the 333 respondents (response rate = 27%), 78% and 40% of 156 respondents declared that they would consider using thoracic epidural analgesia (TEA) and thoracic paravertebral blockade (TPB), respectively. The main benefits declared for performing RA were the ability to have effective analgesia, a more effective cough, and early rehabilitation. For 70% of the respondents, trauma patients with a theoretical indication of RA did not receive TEA or TPB for the following reasons: the ICU had no experience of RA (62%), no anesthesiologist-intensivist working in the ICU (46%), contraindications (27%), ignorance of the SFAR guidelines (19%), and no RA protocol available (13%). In this survey, 95% of the respondents thought the prognosis of trauma patients could be influenced by the use of RA. CONCLUSIONS: While TEA and TPB are underused because of several limitations related to the patterns of injuries in multitrauma patients, lack of both experience and confidence in combination with the absence of available protocols appear to be the major restraining factors, even if physicians are aware that patients' outcomes could be improved by RA. These results suggest the need to strengthen initial training and provide continuing education about RA in the ICU.

Halogenated Agent Delivery in Porcine Model of Acute Respiratory Distress Syndrome via an Intensive Care Unit Type Device.

Acute respiratory distress syndrome (ARDS) is a common cause of hypoxemic respiratory failure and death in critically ill patients, and there is an urgent need to find effective therapies. Preclinical studies have shown that inhaled halogenated agents may have beneficial effects in animal models of ARDS. The development of new devices to administer halogenated agents using modern intensive care unit (ICU) ventilators has significantly simplified the dispensing of halogenated agents to ICU patients. Because previous experimental and clinical research suggested potential benefits of halogenated volatiles, such as sevoflurane or isoflurane, for lung alveolar epithelial injury and inflammation, two pathophysiologic landmarks of diffuse alveolar damage during ARDS, we designed an animal model to understand the mechanisms of the effects of halogenated agents on lung injury and repair. After general anesthesia, tracheal intubation, and the initiation of mechanical ventilation, ARDS was induced in piglets via the intratracheal instillation of hydrochloric acid. Then, the piglets were sedated with inhaled sevoflurane or isoflurane using an ICU-type device, and the animals were ventilated with lung-protective mechanical ventilation during a 4 h period. During the study period, blood and alveolar samples were collected to evaluate arterial oxygenation, the permeability of the alveolar-capillary membrane, alveolar fluid clearance, and lung inflammation. Mechanical ventilation parameters were also collected throughout the experiment. Although this model induced a marked decrease in arterial oxygenation with altered alveolar-capillary permeability, it is reproducible and is characterized by a rapid onset, good stability over time, and no fatal complications. We have developed a piglet model of acid aspiration that reproduces most of the physiological, biological, and pathological features of clinical ARDS, and it will be helpful to further our understanding of the potential lung-protective effects of halogenated agents delivered through devices used for inhaled ICU sedation.

Early Changes Over Time in the Radiographic Assessment of Lung Edema Score Are Associated With Survival in ARDS.

BACKGROUND: The Radiographic Assessment of Lung Edema (RALE) score is associated with the severity of ARDS, and treatments targeted at reducing pulmonary edema such as conservative fluid management cause a reduction in RALE score over time. RESEARCH QUESTION: Are early changes in RALE score over time associated with survival in patients with ARDS? STUDY DESIGN AND METHODS: Data from patients enrolled in three centers in the Lung Imaging for Ventilation sEtting in ARDS (LIVE) trial with available chest radiographs at baseline (day 0) and days 2 or 3 were used. The RALE was scored by two independent reviewers. The primary end point was death by day 90, considering RALE score both at baseline and as a time-varying covariate in a marginal Cox survival model. RESULTS: RALE was scored from 135, 64, and 88 radiographs on days 0, 2, and 3, respectively. Both baseline RALE (hazard ratio [HR] for each one-point increment, 1.04; 95% CI, 1.01-1.08; P = .006) and the change in RALE over time (HR for each one-point decrease per unit of time, 0.99; 95% CI, 0.99-0.99; P = .03) were associated with death by day 90, even after adjustment for age, sex, BMI, Simplified Acute Physiology Score II, vasopressor use, and total volume of fluids received since study entry. INTERPRETATION: The change in RALE during the first days after ARDS onset is independently associated with survival and may be useful as a surrogate end point in future clinical trials of new therapeutics in ARDS.

The receptor for advanced glycation end-products enhances lung epithelial wound repair: An in vitro study.

Re-epithelialization of the alveolar surface is a key process of lung alveolar epithelial barrier repair after acute lung injury. The receptor for advanced glycation end-products (RAGE) pathway plays key roles in lung homeostasis, and its involvement in wound repair has been already reported in human bronchial epithelial cells. However, its effects on lung alveolar epithelial repair after injury remain unknown. We investigated whether RAGE stimulation with its ligands high-mobility group box 1 protein (HMGB1) or advanced glycation end-products (AGEs), alone or associated with RAGE inhibition using RAGE antagonist peptide, affects in vitro wound healing in human alveolar epithelial A549 cells. We further asked whether these effects could be associated with changes in cell proliferation and migration. We found that treatment of A549 cells with HMGB1 or AGEs promotes RAGE-dependent wound healing after a scratch assay. In addition, both RAGE ligands increased cell proliferation in a RAGE-dependent manner. Treatment with HMGB1 increased migration of alveolar epithelial cells at 12 h, independently of RAGE, whereas AGEs stimulated migration as measured 48 h after injury in a RAGE-dependent manner. Taken together, these results suggest that RAGE pathway is involved in lung alveolar epithelial wound repair, possibly through enhanced cell migration and proliferation.

Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis.

BACKGROUND: Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits. METHODS: We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects. DISCUSSION: This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (ID: CRD42019157236).

Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets.

The receptor for advanced glycation end-products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will require assessment of this strategy in larger animals. Forty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid (i) alone; (ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), or (iii) recombinant soluble (s)RAGE. The primary outcome was net AFC at 4 h. Arterial oxygenation was assessed hourly and alveolar-capillary permeability, alveolar inflammation and lung histology were assessed at 4 h. Treatment with either RAP or sRAGE improved net AFC (median [interquartile range], 21.2 [18.8-21.7] and 19.5 [17.1-21.5] %/h, respectively, versus 12.6 [3.2-18.8] %/h in injured, untreated controls), oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after ARDS. These findings suggest that RAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.

High frequency percussive ventilation increases alveolar recruitment in early acute respiratory distress syndrome: an experimental, physiological and CT scan study.

BACKGROUND: High frequency percussive ventilation (HFPV) combines diffusive (high frequency mini-bursts) and convective ventilation patterns. Benefits include enhanced oxygenation and hemodynamics, and alveolar recruitment, while providing hypothetic lung-protective ventilation. No study has investigated HFPV-induced changes in lung aeration in patients with early acute respiratory distress syndrome (ARDS). METHODS: Eight patients with early non-focal ARDS were enrolled and five swine with early non-focal ARDS were studied in prospective computed tomography (CT) scan and animal studies, in a university-hospital tertiary ICU and an animal laboratory. Patients were optimized under conventional "open-lung" ventilation. Lung CT was performed using an end-expiratory hold (Conv) to assess lung morphology. HFPV was applied for 1 hour to all patients before new CT scans were performed with end-expiratory (HFPV EE) and end-inspiratory (HFPV EI) holds. Lung volumes were determined after software analysis. At specified time points, blood gases and hemodynamic data were collected. Recruitment was defined as a change in non-aerated lung volumes between Conv, HFPV EE and HFPV EI. The main objective was to verify whether HFPV increases alveolar recruitment without lung hyperinflation. Correlation between pleural, upper airways and HFPV-derived pressures was assessed in an ARDS swine-based model. RESULTS: One-hour HFPV significantly improved oxygenation and hemodynamics. Lung recruitment significantly rose by 12.0% (8.5-18.0%), P = 0.05 (Conv-HFPV EE) and 12.5% (9.3-16.8%), P = 0.003 (Conv-HFPV EI). Hyperinflation tended to increase by 2.0% (0.5-2.5%), P = 0.89 (Conv-HFPV EE) and 3.0% (2.5-4.0%), P = 0.27 (Conv-HFPV EI). HFPV hyperinflation correlated with hyperinflated and normally-aerated lung volumes at baseline: r = 0.79, P = 0.05 and r = 0.79, P = 0.05, respectively (Conv-HFPV EE); and only hyperinflated lung volumes at baseline: r = 0.88, P = 0.01 (Conv-HFPV EI). HFPV CT-determined tidal volumes reached 5.7 (1.1-8.1) mL.kg-1 of ideal body weight (IBW). Correlations between pleural and HFPV-monitored pressures were acceptable and end-inspiratory pleural pressures remained below 25cmH20. CONCLUSIONS: HFPV improves alveolar recruitment, gas exchanges and hemodynamics of patients with early non-focal ARDS without relevant hyperinflation. HFPV-derived pressures correlate with corresponding pleural or upper airways pressures. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02510105 . Registered on 1 June 2015. The trial was retrospectively registered.

Recent directions in personalised acute respiratory distress syndrome medicine.

Acute respiratory distress syndrome (ARDS) is heterogeneous by definition and patient response varies depending on underlying biology and their severity of illness. Although ARDS subtypes have been identified with different prognoses in past studies, the concept of phenotypes or endotypes does not extend to the clinical definition of ARDS. This has possibly hampered the development of therapeutic interventions that target select biological mechanisms of ARDS. Recently, a major advance may have been achieved as it may now be possible to identify ARDS subtypes that may confer different responses to therapy. The aim of personalised medicine is to identify, select, and test therapies that are most likely to be associated with a favourable outcome in a specific patient. Several promising approaches to ARDS subtypes capable of predicting therapeutic response, and not just prognosis, are highlighted in this perspective paper. An overview is also provided of current and future directions regarding the provision of personalised ARDS medicine. The importance of delivering the right care, at the right time, to the right patient, is emphasised.

RAGE inhibition reduces acute lung injury in mice.

The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.

Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome.

RATIONALE: Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. OBJECTIVES: To verify whether sRAGE could predict AFC during ARDS. METHODS: Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. MEASUREMENTS AND MAIN RESULTS: The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. CONCLUSIONS: Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).