Inhaled Sedation in Patients with COVID-19-Related Acute Respiratory Distress Syndrome: An International Retrospective Study

Background and objectives: The coronavirus disease 2019 (COVID-19) pandemic and the shortage of intravenous sedatives has led to renewed interest in inhaled sedation for patients with acute respiratory distress syndrome (ARDS). We hypothesized that inhaled sedation would be associated with improved clinical outcomes in COVID-19 ARDS patients. Methods: Retrospective international study including mechanically ventilated patients with COVID-19 ARDS who required sedation and were admitted to 10 European and US intensive care units. The primary endpoint of ventilator-free days through day 28 was analyzed using zero-inflated negative binomial regression, before and after adjustment for site, clinically relevant covariates determined according to the univariate results, and propensity score matching. Results: A total of 196 patients were enrolled, 78 of whom died within 28 days. The number of ventilator-free days through day 28 did not differ significantly between the patients who received inhaled sedation for at least 24 h (n = 111) and those who received intravenous sedation only (n = 85), with medians of 0 (interquartile range [IQR] 0–8) and 0 (IQR 0–17), respectively (odds ratio for having zero ventilator-free days through day 28, 1.63, 95% confidence interval [CI], 0.91–2.92, p = 0.10). The incidence rate ratio for the number of ventilator-free days through day 28 if not 0 was 1.13 (95% CI, 0.84–1.52, p = 0.40). Similar results were found after multivariable adjustment and propensity matching. Conclusion: The use of inhaled sedation in COVID-19 ARDS was not associated with the number of ventilator-free days through day 28. Keywords: coronavirus disease 2019; acute respiratory distress syndrome; inhaled sedation; sevoflurane; isofluran

Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data

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. 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. 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 Delta P on mortality but not that of higher V (T). 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)

Rougnat (Creuse). Sondage Saint-Hilaire

Rougnat a eu deux églises paroissiales connues, l’une dédiée à saint Jean Baptiste, existante en 1158 et qui n’était plus qu’une annexe en 1436. Devenue simple chapelle au xviiie s., elle était ruinée au milieu du xixe et n’existe plus aujourd’hui. L’église actuelle est placée sous le vocable de saint Laurent. Le microtoponyme Saint-Hilaire demeure à ce jour une énigme. Il n’est pas impossible qu’une première chapelle ait porté ce nom. Le sondage a permis de mettre au jour un habitat méroving..

Effets du sévoflurane sur les lésions pulmonaires et leur cicatrisation via la voie RAGE : une approche translationnelle

Le syndrome de détresse respiratoire aiguë (SDRA) est un syndrome clinique associé au niveau pulmonaire à une lésion épithéliale diffuse à l’origine de la détresse respiratoire observée. L’altération de la fonction de clairance alvéolaire liquidienne (AFC), liée à l’altération épithéliale et l’inflammation constituent deux caractéristiques pathologiques majeures fréquemment retrouvées au cours du SDRA. Parmis les voies de signalisation misent en jeu, le récepteur des produits de glycation avancée (RAGE) semble être impliqué au cours du SDRA et sa modulation pourrait être bénéfique. Malgré les avancées thérapeutiques en réanimation en termes de ventilation mécanique et de sédation, le SDRA reste fréquent, et est associé à une morbidité et un mortalité importantes. Peu de traitements pharmacologiques spécifiques au SDRA existent à ce jour rendant indispensable de poursuivre les recherches mécanistiques afin de poursuivre le développement de thérapies ciblées. La gestion moderne de la sédation en réanimation privilégie des sédations aussi courtes que possibles et repose sur l’utilisation d’agents sédatifs simples d’utilisation possédant une rapidité d’action, une élimination rapide et sans accumulation. Les agents volatiles halogénés comme le sévoflurane possèdent de nombreuses caractéristiques intrinsèques suggérant une place comme agent de sédation “idéal” dans l'arsenal thérapeutique. Bien que qu’ils soient largement utilisés au bloc opératoire, les données concernant leur utilisation en réanimation au cours du SDRA restent faibles à ce jour. Les objectifs de ce travail étaient de décrire et de caractériser la place de la sédation inhalée au cours du SDRA via une approche translationnelle combinant des études pré-cliniques expérimentales et des études cliniques. Premièrement il a fallu mettre au point des systèmes et des modèles expérimentaux de SDRA permettant d’étudier les effets des agents halogénés sur des cultures cellulaires et sur les animaux. Ensuite, via un modèle expérimental de SDRA chez le cochon, nous avons pu mettre en évidence que comparativement à la sédation intraveineuse, une sédation inhalée par sevoflurane améliorait l’oxygénation via une amélioration de l’AFC, qui était elle-même associée à une restauration des canaux épithéliaux AQP-5, ENac et Na,K,ATP-ase. Nous avons également évaluer l’utilisation de la sédation inhalée en réanimation avant et après la pandémie COVID-19. Parallèlement, les études cliniques ont montré que l’utilisation du sévoflurane était associée à une amélioration de l’oxygénation, de l’AFC et une diminution des lésions épithéliales via une baisse de la forme soluble de RAGE. Ces résultats sont en cours de confirmation sur une plus grande cohorte. L’utilisation de la sédation inhalée a également été évaluée spécifiquement chez les patients COVID-19. Devant certains résultats suggérant un impact de morphologie de l’atteinte pulmonaire au cours du SDRA sur la sédation inhalée, une étude de pharmacocinétique du sévoflurane en fonction du caractère focal ou non-focal du SDRA est en cours de réalisation.L’ensemble de ces résultats montre un intérêt grandissant pour l'utilisation de la sédation inhalée chez les patients de réanimation présentant un SDRA devant des données précliniques et cliniques encourageantes en termes d’amélioration de l’oxygénation et de diminution de lésion épithéliale. Les autres mécanismes mis en jeu, et notamment les voies de signalisation précises impliquées comme la voie RAGE nécessitent d’être étudiées plus précisément. Le sévoflurane apparaît donc comme un nouvel acteur thérapeutique prometteur au cours du SDRA, néanmoins avant de confirmer définitivement la place du sévoflurane dans l’arsenal thérapeutique du SDRA, de nouvelles études cliniques et mécanistiques sont nécessaires.Acute respiratory distress syndrome (ARDS) is a clinical syndrome associated with diffuse epithelial injury that induces hypoxemic failure. Impaired alveolar fluid clearance (AFC), related to epithelial damage, and inflammation are two major pathological features frequently found during ARDS. Among the signaling pathways involved, the receptor for advanced glycation products (RAGE) seems to be involved during ARDS and its modulation could be beneficial. Despite therapeutic advances in intensive care units (ICU) in terms of mechanical ventilation and sedation, ARDS remains frequent and is associated with significant morbidity and mortality. Few pharmacological treatments specific to ARDS exist to date, making it urgent to continue mechanistic research in order to develop new therapies. Modern management of sedation in the ICU strengthens sedation as short as possible using sedative agents that have a rapid onset of action, rapid elimination and no accumulation. Halogenated agents such as sevoflurane have many intrinsic characteristics suggesting a role as an "ideal" sedative agent. Although halogenated agents are widely used in the operating room, poor data concerning their use in the ICU during ARDS are available to date. The objectives of this work were to describe and characterize the place of inhaled sedation in ARDS using a translational approach combining experimental pre-clinical studies and clinical studies. First, we developed systems and experimental models of ARDS to study the effects of halogenated agents in cell cultures and in animals. Secondly, via an experimental model of ARDS in piglets, we demonstrated that inhaled sedation with sevoflurane, compared to intravenous sedation, improved oxygenation via an improvement of AFC, and was associated with a restoration of epithelial AQP-5, ENac and Na,K,ATP-ase channels protein expression. We also evaluated the use of inhaled sedation in intensive care units before and after COVID-19. Furthermore, clinical studies showed that the use of sevoflurane was associated with improved oxygenation, AFC and decreased epithelial damage. These results are being confirmed in a larger cohort of patients. The use of inhaled sedation was also specifically evaluated in COVID-19 patients. As previously demonstrated by our team, the morphology of lung injury during ARDS could impact the inhaled sedation. Consequently, we designed a trial to study the pharmacokinetics of sevoflurane according to the focal or non-focal status of ARDS. All these results demonstrate a growing interest for the use of inhaled sedation in ICU patients. Preclinical and clinical data suggest that inhaled sedation could be beneficial with an improvement of oxygenation and a decrease of epithelial injury. Other mechanisms involved, especially the specific signaling pathways involved, such as the RAGE pathway, need to be more specifically studied. Thus, sevoflurane appears to be a promising new therapeutic agent in ARDS. However, before definitively confirming the place of sevoflurane in the therapeutic arsenal of ARDS, further clinical and mechanistic studies are needed

Encou-RAGE-ing Lung Protection in Patients With Acute Respiratory Distress Syndrome Under Extracorporeal Membrane Oxygenation.

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ARDS in patients with chest trauma: Better safe than sorry.

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Distinct Biological Effects of Time-Controlled Adaptive Ventilation in Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome: "One Small Step for Rats, One Giant Leap for Humans?"

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A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome

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

High-frequency percussive ventilation as a rescue therapy for ARDS patients under ECMO: About a case

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