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Resume L’inhalation continue des agents halogenes tels que l’isoflurane ou le sevoflurane, avec un objectif de sedation, est desormais possible chez le patient en soins critiques, grâce a la disponibilite de vaporisateurs et de systemes de recyclage dedies. Une telle strategie necessite un equipement specifique et une formation appropriee des equipes soignantes. L’isoflurane et le sevoflurane ont des proprietes pharmacologiques adaptees avec des delais d’action et d’elimination rapides, et la sedation par inhalation s’integre bien dans le bundle « ABCDEF » de prise en charge du patient de reanimation. Cette modalite d’administration bien toleree, autorise des niveaux de sedation variables de legere a profonde. En plus de leurs effets sedatifs, ces molecules pourraient egalement presenter des avantages cliniques en termes de protection de certains organes, particulierement pertinents chez les patients de reanimation. Cet article resume les bases pharmacologiques et les modalites pratiques de la sedation inhalee en reanimation, examine les preuves disponibles soutenant la sedation inhalee comme une alternative a la sedation intraveineuse, et discute des zones d’incertitude restantes et des perspectives futures de developpement. more...

ImportanceThe extended Focused Assessment With Sonography for Trauma (E-FAST) has become a cornerstone of the diagnostic workup in patients with trauma. The added value of a diagnostic workup including an E-FAST to support decision-making remains unknown.ObjectiveTo determine how often an immediate course of action adopted in the resuscitation room based on a diagnostic workup that included an E-FAST and before whole-body computed tomography scanning (WBCT) in patients with blunt trauma was appropriate.Design, Setting, and ParticipantsThis cohort study was conducted at 6 French level I trauma centers between November 5, 2018, and November 5, 2019. Consecutive patients treated for blunt trauma were assessed at the participating centers. Data analysis took place in February 2022.ExposuresDiagnostic workup associating E-FAST (including abdominal, thoracic, pubic, and transcranial Doppler ultrasonography scan), systematic clinical examination, and chest and pelvic radiographs.Main Outcomes and MeasuresThe main outcome criterion was the appropriateness of the observed course of action (including abstention) in the resuscitation room according to evaluation by a masked expert panel.ResultsOf 515 patients screened, 510 patients (99.0%) were included. Among the 510 patients included, 394 were men (77.3%), the median (IQR) age was 46 years (29-61 years), and the median (IQR) Injury Severity Score (ISS) was 24 (17-34). Based on the initial diagnostic workup, no immediate therapeutic action was deemed necessary in 233 cases (45.7%). Conversely, the following immediate therapeutic actions were initiated before WBCT: 6 emergency laparotomies (1.2%), 2 pelvic angioembolisations (0.4%), 52 pelvic binders (10.2%), 41 chest drains (8.0%) and 16 chest decompressions (3.1%), 60 osmotherapies (11.8%), and 6 thoracotomies (1.2%). To improve cerebral blood flow based on transcranial doppler recordings, norepinephrine was initiated in 108 cases (21.2%). In summary, the expert panel considered the course of action appropriate in 493 of 510 cases (96.7%; 95% CI, 94.7%-98.0%). Among the 17 cases (3.3%) with inappropriate course of action, 13 (76%) corresponded to a deviation from existing guidelines and 4 (24%) resulted from an erroneous interpretation of the E-FAST.Conclusions and RelevanceThis prospective, multicenter cohort study found that a diagnostic resuscitation room workup for patients with blunt trauma that included E-FAST with clinical assessment and targeted chest and pelvic radiographs was associated with the determination of an appropriate course of action prior to WBCT. more...

The roles of thioredoxin-interacting protein (TXNIP) and receptor for advanced glycation end-products (RAGE)-dependent mechanisms of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-driven macrophage activation during acute lung injury are underinvestigated. Cultured THP-1 macrophages were treated with a RAGE agonist (S100A12), with or without a RAGE antagonist; cytokine release and intracytoplasmic production of reactive oxygen species (ROS) were assessed in response to small interfering RNA knockdowns of TXNIP and NLRP3. Lung expressions of TXNIP and NLRP3 and alveolar levels of IL-1β and S100A12 were measured in mice after acid-induced lung injury, with or without administration of RAGE inhibitors. Alveolar macrophages from patients with acute respiratory distress syndrome and from mechanically ventilated controls were analyzed using fluorescence-activated cell sorting. In vitro, RAGE promoted cytokine release and ROS production in macrophages and upregulated NLRP3 and TXNIP mRNA expression in response to S100A12. TXNIP inhibition downregulated NLRP3 gene expression and RAGE-mediated release of IL-1β by macrophages in vitro. In vivo, RAGE, NLRP3 and TXNIP lung expressions were upregulated during experimental acute lung injury, a phenomenon being reversed by RAGE inhibition. The numbers of cells expressing RAGE, NLRP3 and TXNIP among a specific subpopulation of CD16+CD14+CD206- (“pro-inflammatory”) alveolar macrophages were higher in patients with lung injury. This study provides a novel proof-of-concept of complex RAGE–TXNIP–NLRP3 interactions during macrophage activation in acute lung injury. more...

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 Societe Francaise d'Anesthesie Reanimation (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. more...

Purpose of review This article provides an overview of protein biomarkers for acute respiratory distress syndrome (ARDS) and their potential use in future clinical trials. Recent findings The protein biomarkers studied as indices of biological processes involved in the pathogenesis of ARDS may have diagnostic and/or prognostic value. Recently, they also proved useful for identifying ARDS phenotypes and assessing heterogeneity of treatment effect in retrospective analyses of completed clinical trials. Summary This article summarizes the current research on ARDS biomarkers and provides insights into how they should be integrated as prognostic and predictive enrichment tools in future clinical trials. more...

Inhaled sedation with halogenated agents, such as isoflurane or sevoflurane, is now feasible in intensive care unit (ICU) patients through dedicated vaporisers and scavenging systems. Such a sedation strategy requires specific equipment and adequate training of ICU teams. Isoflurane and sevoflurane have ideal pharmacological properties that allow efficient, well-tolerated, and titratable light-to-deep sedation. In addition to their function as sedative agents, these molecules may have clinical benefits that could be especially relevant to ICU patients. Our goal was to summarise the pharmacological basis and practical aspects of inhaled ICU sedation, review the available evidence supporting inhaled sedation as a viable alternative to intravenous sedation, and discuss the remaining areas of uncertainty and future perspectives of development. more...

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 &lt, 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. more...

The effect of the routine use of a stylet during tracheal intubation on first-attempt intubation success is unclear. We hypothesised that the first-attempt intubation success rate would be higher with tracheal tube + stylet than with tracheal tube alone.In this multicentre randomised controlled trial, conducted in 32 intensive care units, we randomly assigned patients to tracheal tube + stylet or tracheal tube alone (i.e. without stylet). The primary outcome was the proportion of patients with first-attempt intubation success. The secondary outcome was the proportion of patients with complications related to tracheal intubation. Serious adverse events, i.e., traumatic injuries related to tracheal intubation, were evaluated.A total of 999 patients were included in the modified intention-to-treat analysis: 501 (50%) to tracheal tube + stylet and 498 (50%) to tracheal tube alone. First-attempt intubation success occurred in 392 patients (78.2%) in the tracheal tube + stylet group and in 356 (71.5%) in the tracheal tube alone group (absolute risk difference, 6.7; 95%CI 1.4-12.1; relative risk, 1.10; 95%CI 1.02-1.18; P = 0.01). A total of 194 patients (38.7%) in the tracheal tube + stylet group had complications related to tracheal intubation, as compared with 200 patients (40.2%) in the tracheal tube alone group (absolute risk difference, - 1.5; 95%CI - 7.5 to 4.6; relative risk, 0.96; 95%CI 0.83-1.12; P = 0.64). The incidence of serious adverse events was 4.0% and 3.6%, respectively (absolute risk difference, 0.4; 95%CI, - 2.0 to 2.8; relative risk, 1.10; 95%CI 0.59-2.06. P = 0.76).Among critically ill adults undergoing tracheal intubation, using a stylet improves first-attempt intubation success. more...

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 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. more...

International audience; Purpose: The effect of the routine use of a stylet during tracheal intubation on first-attempt intubation success is unclear. We hypothesised that the first-attempt intubation success rate would be higher with tracheal tube + stylet than with tracheal tube alone.Methods: In this multicentre randomised controlled trial, conducted in 32 intensive care units, we randomly assigned patients to tracheal tube + stylet or tracheal tube alone (i.e. without stylet). The primary outcome was the proportion of patients with first-attempt intubation success. The secondary outcome was the proportion of patients with complications related to tracheal intubation. Serious adverse events, i.e., traumatic injuries related to tracheal intubation, were evaluated.Results: A total of 999 patients were included in the modified intention-to-treat analysis: 501 (50%) to tracheal tube + stylet and 498 (50%) to tracheal tube alone. First-attempt intubation success occurred in 392 patients (78.2%) in the tracheal tube + stylet group and in 356 (71.5%) in the tracheal tube alone group (absolute risk difference, 6.7; 95%CI 1.4-12.1; relative risk, 1.10; 95%CI 1.02-1.18; P = 0.01). A total of 194 patients (38.7%) in the tracheal tube + stylet group had complications related to tracheal intubation, as compared with 200 patients (40.2%) in the tracheal tube alone group (absolute risk difference, - 1.5; 95%CI - 7.5 to 4.6; relative risk, 0.96; 95%CI 0.83-1.12; P = 0.64). The incidence of serious adverse events was 4.0% and 3.6%, respectively (absolute risk difference, 0.4; 95%CI, - 2.0 to 2.8; relative risk, 1.10; 95%CI 0.59-2.06. P = 0.76).Conclusions: Among critically ill adults undergoing tracheal intubation, using a stylet improves first-attempt intubation success. more...

International audience; 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. more...

IntroductionRecently, fluid collected from the heat-and-moisture-exchange filters, which are commonly used in most mechanically ventilated patients under intravenous sedation, has been reported as a potential surrogate for fluid in the distal airspace. Therefore, collection of this fluid represents a promising, non-invasive method for sampling the distal airspace in patients with acute respiratory distress syndrome (ARDS) and for facilitating a mechanistic understanding of this devastating disease. The current study protocol was constructed to assess whether this fluid could be sampled from a dedicated device (Anaesthetic Conserving Device [AnaConDa-S], Sedana Medical, Danderyd, Sweden) used to deliver inhaled sevoflurane for sedation in patients with ARDS.Methods and analysisA total of 30 adult patients within 24 hours of meeting the Berlin criteria for moderate-severe ARDS and receiving inhaled sevoflurane as standard sedation in participating centres will be eligible for inclusion into this investigator-initiated, exploratory, prospective, bicentre study. After at least 12 h of inhaled sedation, a sample of directly aspirated, undiluted pulmonary oedema fluid will be collected concurrently with fluid from the AnaConDa-S device. Levels of proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α and sTNFr-1) and markers of lung endothelial (Ang-2) and epithelial (sRAGE) injury will be measured in both fluids by Multiplex. The primary endpoint is the correlation between protein markers (IL-1β, IL-6, IL-8, TNF-α, sTNFr-1, Ang-2 and sRAGE) measured in the undiluted pulmonary oedema fluid versus the AnaConDa-S fluid.Ethics and disseminationThe study was approved by the appropriate ethics committee (CPP Est I). Informed consent is required. The fluid collection from the AnaConDa-S has potential to foster our understanding of the potential effects of inhaled sedation in clinical ARDS and to open up novel perspectives for prognostic and predictive enrichment in future trials. The results will be published in a peer-reviewed journal.Registration numberNCT03964155. more...

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). more...

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. more...

Background and objective Elevated driving pressure (ΔP) may be associated with increased risk of acute respiratory distress syndrome (ARDS) in patients admitted via the emergency department and with post-operative pulmonary complications in surgical patients. This study investigated the association of higher ΔP with the onset of ARDS in a high-risk, intensive care unit (ICU) population. Methods This is a secondary analysis of a prospective multicentre observational study. Data for this ancillary study were obtained from intubated adult patients with at least one ARDS risk factor upon ICU admission enrolled in a previous multicentre observational study. Patients were followed up for the development of ARDS within 7 days (primary outcome). Univariate and multivariate analyses tested the association between ΔP (measured at ICU admission (baseline) or 24 h later (day 1)) and the development of ARDS. Results A total of 221 patients were included in this study, among whom 34 (15%) developed ARDS within 7 days. These patients had higher baseline ΔP than those who did not (mean ± SD: 12.5 ± 3.1 vs 9.8 ± 3.4 cm H2 O, respectively, P = 0.0001). The association between baseline ΔP and the risk of developing ARDS was robust to adjustment for baseline tidal volume, positive-end expiratory pressure, illness severity, serum lactate and sepsis, pneumonia, severe trauma and shock as primary ARDS risk factors (odds ratio: 1.20; 95% CI: 1.03-1.41; P = 0.02). The same results were found with day 1 ΔP. Conclusion Among at-risk ICU patients, higher ΔP may identify those who are more likely to develop ARDS. more...

Resume Certains reglages du respirateur comme la fraction inspiree en oxygene, le debit d’insufflation, le reglage d’une pause tele-inspiratoire, le rapport entre le temps inspiratoire et le temps expiratoire, ainsi que d’autres reglages specifiques aux modes ventilatoires assistes ont moins fait l’objet d’etudes cliniques que le reglage du volume courant ou de la pression tele-expiratoire positive par exemple. Pourtant, ces reglages, dits « caches », peuvent avoir un impact majeur sur l’efficacite de la ventilation ainsi que sur le confort et le travail respiratoire du patient. L’interet principal de bien connaitre ses reglages est de toujours chercher, lorsque cela est possible, d’adapter le respirateur au patient et non d’adapter le patient au respirateur. more...

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. more...

International audience; 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. more...

The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn’s disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity. more...

BackgroundThe receptor for advanced glycation end products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition was recently associated with attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will first require assessment of this strategy in larger animals.MethodsForty-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), a S100P-derived peptide that prevents activation of RAGE by its ligands, or iii) in combination with intravenous administration of recombinant soluble (s)RAGE that acted as a decoy receptor. The primary outcome measure was net AFC at 4 h. Arterial oxygenation was assessed hourly for 4 h and alveolar-capillary permeability, alveolar inflammation, lung histology and lung mRNA expression of the epithelial sodium channel (α1-ENaC), α1-Na,K-ATPase and aquaporin (AQP)-5 were assessed at 4 h.FindingsTreatment with either RAP or sRAGE improved net AFC rates (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), improved oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after acid-induced ARDS. RAGE inhibition also restored lung mRNA expression of α1-Na,K-ATPase and AQP-5.InterpretationRAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.FundingAuvergne Regional Council, Agence Nationale de la Recherche, Direction Générale de l’Offre de Soins.Research in ContextEvidence before this studyThe acute respiratory distress syndrome (ARDS), a clinical syndrome of diffuse pulmonary oedema and inflammation, currently lacks effective therapies and is associated with high mortality and morbidity. The degrees of lung epithelial injury and of alveolar fluid clearance (AFC) impairment, as evaluated by plasma levels of soluble receptor for glycation end-products (RAGE), are major prognostic factors in ARDS and potential therapeutic targets for ongoing research. For example, targeting RAGE with recombinant sRAGE or an anti-RAGE monoclonal antibody has proven beneficial in a translational mouse model of acid-induced ARDS.Added value of this studyIn a piglet model of acid-induced ARDS, treatment with RAGE antagonist peptide or recombinant sRAGE restored AFC and attenuated the features of lung injury, thereby confirming, in the closest evolutionary model species to humans, previous evidence from rodent models that modulation of RAGE may be a therapeutic option for ARDS. Although this is an important step towards future clinical translation, future studies should assess the best methods to modulate RAGE and further confirm the safety of manipulating this pathway in patients with ARDS. more...

Acute respiratory distress syndrome (ARDS) is a syndrome of diffuse alveolar injury with impaired alveolar fluid clearance and severe inflammation. The use of halogenated agents, such as sevoflurane or isoflurane, for the sedation of intensive care unit (ICU) patients can improve gas exchange, reduce alveolar edema, and attenuate inflammation during ARDS. However, data on the use of inhaled agents for continuous sedation in the ICU to treat or prevent lung damage is lacking. To study the effects of halogenated agents on alveolar epithelial cells under "physiologic" conditions, we describe an easy system to culture cells at the air-liquid interface and expose them to halogenated agents to provide precise controlled "air" fractions and "medium" concentrations for these agents. We developed a sealed air-tight chamber in which plates with human alveolar epithelial immortalized cells could be exposed to a precise, controlled fraction of sevoflurane or isoflurane using a continuous gas flow provided by an anesthetic machine circuit. Cells were exposed to 4% of sevoflurane and 1% of isoflurane for 24 hours. Gas mass spectrometry was performed to determine the concentration of halogenated agents dissolved in the medium. After the first hour, the concentrations of sevoflurane and isoflurane in the medium were 251 mg/L and 25 mg/L, respectively. The curves representing the concentrations of both sevoflurane and isoflurane dissolved in the medium showed similar courses over time, with a plateau reached at one hour after exposure. This protocol was specifically designed to reach precise and controlled concentrations of sevoflurane or isoflurane in vitro to improve our understanding of mechanisms involved in epithelial lung injury during ARDS and to test novel therapies for the syndrome. more...

International audience; 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. more...

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International audience; Acute respiratory distress syndrome (ARDS) is an acute-onset hypoxic condition with radiographic bilateral lung infiltration. It is characterized by an acute exudative phase combining diffuse alveolar damage and lung edema followed by a later fibroproliferative phase. Despite an improved understanding of ARDS pathobiology, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help to identify patients at the highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. After a short description of ARDS pathobiology, here, we review the scientific evidence that supports the value of various ARDS biomarkers with regard to their major biological roles in ARDS-associated lung injury and/or repair. Ongoing research aims at identifying and characterizing novel biomarkers, in order to highlight relevant mechanistic explorations of lung injury and repair, and to ultimately develop innovative therapeutic approaches for ARDS patients. This review will focus on the pathophysiologic, diagnostic, and therapeutic implications of biomarkers in ARDS and on their utility to ultimately improve patient care. more...

Purpose: The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury. Methods: We conducted a meta-analysis of individual data from 746 patients enrolled in eight prospective randomized and observational studies in which plasma sRAGE was measured in ARDS articles published through March 2016. The primary outcome was 90-day mortality. Using multivariate and mediation analyses, we tested the association between baseline plasma sRAGE and mortality, independently of driving pressure and tidal volume. Results: Higher baseline plasma sRAGE [odds ratio (OR) for each one-log increment, 1.18; 95% confidence interval (CI) 1.01–1.38; P = 0.04], driving pressure (OR for each one-point increment, 1.04; 95% CI 1.02–1.07; P = 0.002), and tidal volume (OR for each one-log increment, 1.98; 95% CI 1.07–3.64; P = 0.03) were independently associated with higher 90-day mortality in multivariate analysis. Baseline plasma sRAGE mediated a small fraction of the effect of higher ΔP on mortality but not that of higher VT. Conclusions: Higher baseline plasma sRAGE was associated with higher 90-day mortality in patients with ARDS, independently of driving pressure and tidal volume, thus reinforcing the likely contribution of alveolar epithelial injury as an important prognostic factor in ARDS. Registration: PROSPERO (ID: CRD42018100241). © 2018, The Author(s). more...

International audience; Acute respiratory distress syndrome (ARDS) prediction remains challenging despite available clinical scores. To assess soluble receptor for advanced glycation end-products (sRAGE), a marker of lung epithelial injury, as a predictor of ARDS in a high-risk population, adult patients with at least one ARDS risk factor upon admission to participating intensive care units (ICUs) were enrolled in a multicentre, prospective study between June 2014 and January 2015. Plasma sRAGE and endogenous secretory RAGE (esRAGE) were measured at baseline (ICU admission) and 24 hours later (day one). Four AGER candidate single nucleotide polymorphisms (SNPs) were also assayed because of previous reports of functionality (rs1800625, rs1800624, rs3134940, and rs2070600). The primary outcome was ARDS development within seven days. Of 500 patients enrolled, 464 patients were analysed, and 59 developed ARDS by day seven. Higher baseline and day one plasma sRAGE, but not esRAGE, were independently associated with increased ARDS risk. AGER SNP rs2070600 (Ser/Ser) was associated with increased ARDS risk and higher plasma sRAGE in this cohort, although confirmatory studies are needed to assess the role of AGER SNPs in ARDS prediction. These findings suggest that among at-risk ICU patients, higher plasma sRAGE may identify those who are more likely to develop ARDS. Acute respiratory distress syndrome (ARDS) still carries a high mortality rate 1,2 , and a major challenge in targeting the prevention and early treatment of ARDS is the inability to accurately predict which patients will develop the syndrome 3-6. The Lung Injury Prediction Score (LIPS) was developed to identify patients at high risk of developing ARDS; however, its positive predictive value is limited (0.14-0.23) 7. To improve prediction, one method may be to combine clinical data with plasma biomarkers that reflect the pathogenesis of ARDS such as angiopoietin-2 (Ang-2), a marker of lung endothelial injury 8. In contrast, the soluble receptor for advanced gly-cation end-products (sRAGE), a marker of lung epithelial injury 9 , may predict ARDS more accurately in selected at-risk patients, e.g. after cardiac surgery 10 , severe trauma 11 , or after major surgery 12. Soluble forms of RAGE (sRAGE) include the extracellular domain of membrane RAGE that is cleaved by proteinases 13 and endogenous secretory RAGE (esRAGE), among other forms produced by alternative splicing 14,15. sRAGE has good diagnostic value for ARDS and is associated with lung injury severity, the degree of lung epithelial injury, impaired alveolar fluid clearance, and prognosis in ARDS 16,17. Although it remains unclear whether esRAGE may be involved in ligand binding or may have any functional effects by itself, esRAGE levels were lower in the plasma and alveolar fluid from patients with ARDS than in mechanically ventilated controls without ARDS in a previous study 18. In addition, and although not yet ready for clinical use, genomic applications could facilitate better prediction more...

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. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1924-6) contains supplementary material, which is available to authorized users. more...

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International audience; Purpose We used a human corneal epithelial cell (HCE) line to determine the involvement of the advanced glycation end products (AGEs) / receptor for AGEs (RAGE) couple in corneal epithelium wound healing. Methods After wounding, HCE cells were exposed to two major RAGE ligands (HMGB1 and AGEs), and wound healing was evaluated using the in vitro scratch assay. Following wound healing, the HCE cells were used to study the influence of the RAGE ligands on HCE proliferation, invasion, and migration. Activation of the nuclear factor (NF)-κB signaling pathway by the AGEs/RAGE couple was tested using a luciferase reporter assay. Functional transcriptional regulation by this pathway was confirmed by quantification of expression of the connexin 43 target gene. For each experiment, specific RAGE involvement was confirmed by small interfering RNA treatments. Results AGEs treatment at a dose of 100 µg/mL significantly improved the wound healing process in a RAGE-dependent manner by promoting cell migration, whereas HMGB1 had no effect. No significant influence of the AGEs/RAGE couple was observed on cell proliferation and invasion. However, this treatment induced an early activation of the NF-κB pathway and positively regulated the expression of the target gene, connexin 43, at both the mRNA and protein levels. Conclusions Our results demonstrate that the RAGE pathway is activated by AGEs treatment and is involved in the promotion of corneal epithelial wound healing. This positive action is observed only during the early stages of wound healing, as illustrated by the quick activation of the NF-κB pathway and induction of connexin 43 expression. more...

Resume Objectifs La tracheotomie est une procedure frequente en reanimation, mais le devenir post-reanimation des patients est peu documente. Nous avons realise une enquete declarative de pratique aupres de reanimateurs francais exercant en reanimation polyvalente et a orientation neurologique concernant les patients tracheotomises en reanimation et leur devenir post-reanimation. Type d’etude Etude observationnelle descriptive transversale nationale de type enquete d’opinion et de pratique. Materiel et methodes Un courriel a ete adresse a deux medecins de chaque reanimation francaise identifiee. Le questionnaire comprenait des donnees demographiques et relevait les pratiques concernant les indications, la technique et la gestion post-reanimation. Resultats Cent quarante-huit reponses de praticiens de services differents ont ete obtenues dont 15 % de neuroreanimateurs. Il n’y avait pas de difference entre reanimateurs polyvalents et neuroreanimateurs concernant le recours declare a la tracheotomie (10 ± 13 % vs 20 ± 22 % ; p = 0,05) et le delai de realisation (majoritairement entre j10 et j21). Les indications rapportees etaient les echecs de sevrage respiratoire et dysfonctions ventilatoires d’origine neurologique. La technique declaree etait majoritairement percutanee. Seulement 48 % des praticiens declaraient parvenir a sevrer la canule. Des difficultes pour le transfert post-reanimation etaient retrouvees 4 fois sur 5. Quatre-vingt-neuf pour cent des medecins interroges estimaient que cette prise en charge pourrait etre amelioree. Conclusion Les tracheotomies sont frequentes, majoritairement realisees par voie percutanee. Les indications et delais declares correspondent aux recommandations. Les difficultes ressenties de prise en charge et de gestion post-reanimation sont importantes a l’echelon national. more...

Background The acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that encompasses multiple phenotypes, e.g. with regards to lung morphology as assessed by computed tomography (CT). Focal or non-focal lung morphology may influence the response to positive end-expiratory pressure (PEEP), recruitment manoeuvres and prone position. Lung morphology has been hypothesized to be associated with alveolar fluid clearance (AFC), thus explaining various responses to such therapeutic interventions; however, this hypothesis has not been specifically studied in humans. Methods We measured net AFC rates in 30 patients with ARDS as a secondary data analysis of a prospective single-centre study. Net AFC rates were compared between patients with focal ARDS and those with non-focal ARDS, as assessed by lung CT-scans. Results Net AFC rates were significantly lower in patients with non-focal ARDS (n = 23; median [interquartile range], 1.5 [0–5.5] %/h) as compared to those with focal ARDS (n = 7; 10.3 [4.5–15] %/h) (P = 0.01). The area under the receiver-operating characteristic curve when net AFC rates were used to differentiate the presence from absence of non-focal ARDS was 0.93 (95% confidence interval, 0.81–1). Tidal volumes and PEEP levels differed between focal and non-focal ARDS patients, but there was no difference in arterial oxygenation or in alveolar-capillary permeability. Conclusions Non-focal lung morphology may be characterized by a functional endotype consistent with marked AFC impairment. Despite study limitations and the need for validating studies in larger cohorts, such novel findings may reinforce our understanding of the association between ARDS phenotypes and therapeutic responses. more...

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.To verify whether sRAGE could predict AFC during ARDS.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.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.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). more...

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Introduction Le recepteur des produits de glycation avancee (RAGE) exprime a la surface des pneumocytes de type 1 joue un role dans la pathogenie du syndrome de detresse respiratoire aigue (SDRA). sRAGE est sa forme soluble et est un marqueur de la severite de l’atteinte pulmonaire. L’administration intraperitoneale d’une forme recombinante de sRAGE ameliore les lesions alveolaires dans un modele murin de SDRA. L’administration d’anticorps anti-RAGE ameliore la survie dans un modele murin de sepsis. Toutefois, la multiplicite des modeles experimentaux n’a permis a ce jour d’evaluer ni les effets biologiques ni l’efficacite de la modulation de RAGE au cours d’une agression alveolaire directe. Materiel et methodes La lesion alveolaire est evaluee chez des souris anesthesiees ayant subi une instillation d’acide chlorhydrique (HCl) ou non (SHAM) (n = 6–8 par groupe et par temps). L’atteinte pulmonaire est evaluee le jour de l’instillation (j0) puis a j1, j2 et j4, apres une periode de ventilation mecanique standardisee, sur des caracteristiques majeures du SDRA : l’hypoxemie, la reponse inflammatoire alveolaire et l’alteration de la permeabilite alveolocapillaire. Les effets d’une inhibition de l’activation de RAGE sont evalues sur ces criteres apres administration d’une forme recombinante de sRAGE ou d’un anticorps monoclonal anti-RAGE. Resultats L’instillation d’HCl s’accompagne d’un index de permeabilite alveolaire significativement plus eleve a j1 (20,2 [4,8–32,8] %) et j2 (10,4 [5,4–14,1] %) que dans le groupe SHAM (1,3 [0,4–1,9] %) (p Fig. 1 ). Discussion Une strategie d’inhibition de RAGE, par anticorps monoclonal anti-RAGE ou sRAGE recombinant, s’accompagne dans notre modele murin translationnel de lesion epitheliale directe d’une amelioration de l’oxygenation arterielle associee a une diminution de l’inflammation et de la permeabilite alveolaires. Les modalites therapeutiques d’une inhibition de RAGE, ainsi que la capacite de translation clinique de ces resultats preliminaires, restent toutefois a preciser. more...

Introduction Le recepteur des produits de glycation avancee (RAGE) est un recepteur transmembranaire exprime a la surface des pneumocytes de type I dont l’activation semble fortement impliquee dans l’atteinte pulmonaire du syndrome de detresse respiratoire aigue (SDRA) [1] , [2] . Il a ete recemment montre que RAGE participait a la resorption de l’œdeme alveolaire en modulant la clairance alveolaire liquidienne (AFC, pour alveolar fluid clearance) par l’intermediaire des canaux ENaC [3] . L’objectif de notre travail etait de determiner si une inhibition de la voie RAGE regulait l’AFC dans un modele murin de SDRA par lesion epitheliale directe. Materiel et methodes Etude experimentale animale sur 60 souris mâles C57BL/6JT reparties en 4 groupes : trois groupes subissant une instillation intratracheale d’acide chlorhydrique et un groupe temoin « SHAM ». Les groupes instilles par l’acide chlorhydrique etaient divisees en un groupe « HCl » subissant une instillation seule d’acide chlorhydrique, un groupe « mAb » recevant en plus un traitement intraveineux par anticorps monoclonal anti-RAGE et un groupe « R », recevant en plus un traitement intraperitoneal par proteine sRAGE recombinante. j0 determinait le jour de l’instillation et du traitement pour les groupes mAb et R. A des temps specifiques (j0, j1, j2, j4), les souris recevaient, sous anesthesie generale, une instillation intratracheale d’albumine bovine avant d’etre mises sous ventilation mecanique durant 30 minutes. Apres sacrifice, le liquide alveolaire et le sang etaient preleves. L’AFC etait calculee par la difference de concentrations en proteines totales dans le liquide alveolaire avant et a la fin de la periode de ventilation. Resultats L’AFC dans le groupe temoin etait de 36 % sur 30 minutes. L’AFC etait significativement alteree a j1 (8 % p = 0,0006) et a j2 (9 % p = 0,005) dans le groupe HCl. L’inhibition de RAGE etait associee a une elevation significative de l’AFC a j1 par rapport au groupe HCl, dans les groupes mAb (8 % vs 36 %, p = 0,009) et R (8 % vs 37 %, p = 0,009). Tous temps confondus, une correlation significative entre l’AFC et les concentrations plasmatiques de sRAGE etait retrouvee (coefficient de Spearman −0,62) (IC95 [−0,78 : −0,39] p Fig. 1 ). Discussion Nos resultats suggerent qu’une inhibition de la voie RAGE pourrait ameliorer la fonction de clairance alveolaire liquidienne a j1 et a j2 d’une agression alveolaire dans notre modele murin. L’AFC est correlee avec le sRAGE plasmatique, ce qui pourrait renforcer la position de sRAGE comme biomarqueur de l’agression alveolaire au cours du SDRA. Ces resultats preliminaires suggerent l’inhibition de RAGE comme une cible therapeutique potentielle au cours du SDRA. Ces resultats necessitent d’etre confirmes et soulignent l’interet de preciser les liens biologiques entre la voie RAGE et l’AFC. more...

Dear Editor, Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis and to improve the survival of mechanically ventilated hematology patients with invasive pulmonary aspergillosis (IPA) [1]. Cardiac adverse effects can occur, but only cases of tachycardia have been described with voriconazole. Here, we report the cases of three patients admitted to the Intensive Care Unit (ICU) with suspected voriconazoleinduced bradycardia. A 63-year-old woman was admitted for pneumonia (Escherichia coli) with septic shock. She had prolonged neutropenia due to chemotherapy for a diffuse large-cell lymphoma. On day 7, an IPA was suspected, and antifungal therapy with voriconazole was started. Two days following the initiation of voriconazole therapy, we observed multiple episodes of spontaneous bradycardia (20–25 beats/ min) and a QTc up to 0.40 s. As voriconazole was the only change in the patient’s therapeutic regimen, we discontinued the administration of voriconazole and switched her to caspofungin. Normalization of the heart rate occurred during the next day and continued until discharge from the ICU. A 52-year-old woman with chemotherapy-induced myelosuppression was administered voriconazole (400 mg twice per day) for suspected IPA. The diagnosis was confirmed by a computed tomography scan, increased bronchoalveolar lavage antigens and positive test result of sputum for Aspergillus fumigatus. After 4 days of voriconazole therapy, the patient developed arrhythmias followed by sinus bradycardia (QTc = 0.38 s) that required atropine. The replacement of voriconazole with caspofungin was followed by resolution of bradycardia. A 78-year-old man was admitted to the ICU for acute respiratory failure after abdominal surgery. One month later IPA due to Aspergillus fumicatus was diagnosed. Voriconazole therapy was initiated (400 mg twice per day). He also received propofol, remifentanil, haloperidol, nefopam, piperacillin–tazobactam and gabapentine. Three days later, however, the patient experienced several episodes of spontaneous and extreme bradycardia with complete atrioventricular block and a QTc up to 0.36 s on the electrocardiogram (Fig. 1), requiring the administration of isoprenaline. The serum potassium level was 3.6 mmol/L. Voriconazole was administrated intravenously at 300 mg twice per day for 1 week. Plasma voriconazole concentrations (as determined by high-performance liquid chromatography) were 2.86, 3.08 and 3.20 mg/L on the first 3 days following the initiation of therapy, respectively (normal range 1–5.5 mg/L) [2]. We replaced voriconazole with caspofungin, and the patient recovered a sinus cardiac rhythm after 12 h, which he maintained up to discharge from the ICU without any new episodes. In these three patients, severe episodes of bradycardia were not associated with QTc prolongation, torsades de pointes or ventricular tachycardia. All patients were treated more...