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BackgroundThe antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in hospitalised patients with COVID-19, with indication of oxygen and/or ventilator support. Following prior publication of preliminary results, here we present the final results after completion of data monitoring.MethodsIn this European multicentre, open-label, parallel-group, randomised, controlled trial (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care (SoC) alone or in combination with remdesivir, lopinavir/ritonavir, lopinavir/ritonavir and IFN-β-1a, or hydroxychloroquine. Adult patients hospitalised with COVID-19 were eligible if they had clinical evidence of hypoxemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzyme, severe chronic kidney disease, any contra-indication to one of the studied treatments or their use in the 29 days before randomization, or use of ribavirin, as well as pregnancy or breast-feeding. Here, we report results for remdesivir + SoC versus SoC alone. Remdesivir was administered as 200 mg infusion on day 1, followed by once daily infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. Treatment assignation was performed via web-based block randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population.FindingsBetween March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 843 participants were included for the evaluation of remdesivir (control, n=423; remdesivir, n=420).At day 15, the distribution of the WHO ordinal scale was as follow in the remdesivir and control groups, respectively: Not hospitalized, no limitations on activities: 62/420 (14.8%) and 72/423 (17.0%); Not hospitalized, limitation on activities: 126/420 (30%) and 135/423 (31.9%); Hospitalized, not requiring supplemental oxygen: 56/420 (13.3%) and 31/423 (7.3%); Hospitalized, requiring supplemental oxygen: 75/420 (17.9%) and 65/423 (15.4%); Hospitalized, on non-invasive ventilation or high flow oxygen devices: 16/420 (3.8%) and 16/423 (3.8%); Hospitalized, on invasive mechanical ventilation or ECMO: 64/420 (15.2%) and 80/423 (18.9%); Death: 21/420 (5%) and 24/423 (5.7%). The difference between treatment groups was not statistically significant (OR for remdesivir, 1.02, 95% CI, 0.62 to 1.70, P=0.93). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups (remdesivir, n=147/410, 35.9%, versus control, n=138/423, 32.6%, p=0.29).InterpretationRemdesivir use for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15.FundingEuropean Union Commission, French Ministry of Health, DIM One Health Île-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE), AGMT gGmbH, FEDER “European Regional Development Fund”, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Remdesivir was provided free of charge by Gilead.

Supplemental digital content is available in the text., Introduction Avoiding coronavirus disease 2019 (COVID-19) work-related infection in frontline healthcare workers is a major challenge. A massive training program was launched in our university hospital for anesthesia/intensive care unit and operating room staff, aiming at upskilling 2249 healthcare workers for COVID-19 patients' management. We hypothesized that such a massive training was feasible in a 2-week time frame and efficient in avoiding sick leaves. Methods We performed a retrospective observational study. Training focused on personal protective equipment donning/doffing and airway management in a COVID-19 simulated patient. The educational models used were in situ procedural and immersive simulation, peer-teaching, and rapid cycle deliberate practice. Self-learning organization principles were used for trainers' management. Ordinary disease quantity in full-time equivalent in March and April 2020 were compared with the same period in 2017, 2018, and 2019. Results A total of 1668 healthcare workers were trained (74.2% of the target population) in 99 training sessions over 11 days. The median number of learners per session was 16 (interquartile range = 9–25). In the first 5 days, the median number of people trained per weekday was 311 (interquartile range = 124–385). Sick leaves did not increase in March to April 2020 compared with the same period in the 3 preceding years. Conclusions Massive training for COVID-19 patient management in frontline healthcare workers is feasible in a very short time and efficient in limiting the rate of sick leave. This experience could be used in the anticipation of new COVID-19 waves or for rapidly preparing hospital staff for an unexpected major health crisis.

Resume Le College national des enseignants d’anesthesie et de reanimation (CNEAR) reunit les 181 professionnels hospitalo-universitaires de l’anesthesie-reanimation impliques dans l’enseignement et la recherche en anesthesie, reanimation et medecine perioperatoire. Les objectifs du CNEAR pour la discipline anesthesie-reanimation & medecine peri-operatoire sont avant tout pedagogiques, a destination des etudiants du troisieme et du deuxieme cycle des etudes medicales. Le CNEAR intervient ainsi dans l’organisation, l’evaluation et la validation de l’enseignement du troisieme cycle des specialites medicales. Il realise la publication d’un referentiel actualise de connaissances a destination des etudiants du deuxieme cycle des etudes medicales. Grâce a un partenariat fort avec l’universite numerique en sante et sport (UNESS), le CNEAR assure la mise en ligne de contenus pedagogiques sur la plateforme SIDES NG, la mise en place du livret electronique de l’interne et le suivi regulier du curriculum des internes. Les membres du CNEAR participent egalement a la representation de la discipline aupres des pouvoirs publics et des tutelles au sein du Conseil national professionnel d’anesthesie-reanimation et medecine peri-operatoire (CNP-ARMPO). Pour atteindre ces objectifs, le CNEAR travaille en etroite collaboration avec la sous-section 48-01 (Anesthesie-reanimation et medecine peri-operatoire) du Conseil national des universites et la Societe francaise d’anesthesie et de reanimation (SFAR). Il est par ailleurs membre de droit du CNP-ARMPO et de la Coordination nationale des colleges d’enseignants en medecine (CNCEM) et etend ses collaborations internationales grâce a un partenariat prometteur avec UNESS-International.

Resume Pour une revue medicale, la diffusion a grande echelle de chacun de ses articles est aujourd’hui indispensable pour toucher un large public scientifique. Dans ce contexte, l’utilisation du reseau social Twitter permet a chaque nouvelle publication d’etre diffusee tres rapidement, a faible cout, pour des lecteurs precis et partout dans le monde. C’est de loin le reseau social le plus utilise pour partager les publications en 2021. Les reflexions autour de ce sujet ont ainsi abouti a la creation en novembre 2020 de la Social Media Team (SoMe Team) d’Anaesthesia Critical Care and Pain Medicine, le journal anglophone international de la Societe francaise d’anesthesie et de reanimation (SFAR). Cette equipe est coordonnee par un editeur en charge des reseaux sociaux, en lien direct avec le redacteur en chef du journal. Il elabore le planning des tweets en fonction du programme de publication du journal, il fleche le type de contenu qui y sera associe et sollicite les auteurs pour l’obtention d’images ou de courtes videos de presentation de leur publication. Le contenu graphique et la diffusion sur Twitter sont assures par les membres de l’equipe dediee aux reseaux sociaux.

Objectives Patients on venoarterial extracorporeal membrane oxygenation have many risk factors for pulmonary complications in addition to their heart failure. Optimal positive end-expiratory pressure is unknown in these patients. The aim was to evaluate the ability of electrical impedance tomography to help the physician to select the optimal positive end-expiratory pressure in venoarterial extracorporeal membrane oxygenation treated and mechanically ventilated patients during a positive end-expiratory pressure trial. Design Observational prospective monocentric. Setting University hospital. Patients Patients (n = 23) older than 18 years old, on mechanical ventilation and venoarterial extracorporeal membrane oxygenation. Interventions A decreasing positive end-expiratory pressure trial (20-5 cm H2O) in increments of 5 cm H2O was performed and monitored by a collection of clinical parameters, ventilatory and ultrasonographic (cardiac and pulmonary) to define an optimal positive end-expiratory pressure according to respiratory criteria (optimal positive end-expiratory pressure selected by physician with respiratory parameters), and then adjusted according to hemodynamic and cardiac tolerances (optimal positive end-expiratory pressure selected by physician with respiratory, hemodynamic, and echocardiographic parameters). At the same time, electrical impedance tomography data (regional distribution of ventilation, compliance, and overdistension collapse) were recorded and analyzed retrospectively to define the optimal positive end-expiratory pressure. Measurements and main results The median of this optimal positive end-expiratory pressure was 10 cm H2O in our population. Electrical impedance tomography showed that increasing positive end-expiratory pressure promoted overdistention of ventral lung, maximum at positive end-expiratory pressure 20 cm H20 (34% [interquartile range, 24.5-40]). Decreasing positive end-expiratory pressure resulted in collapse of dorsal lung (29% [interquartile range, 21-45.8]). The optimal positive end-expiratory pressure selected by physician with respiratory parameters was not different from the positive end-expiratory pressure chosen by the electrical impedance tomography. However, there is a negative impact of a high level of intrathoracic pressure on hemodynamic and cardiac tolerances. Conclusions Our results support that electrical impedance tomography appears predictive to define optimal positive end-expiratory pressure on venoarterial extracorporeal membrane oxygenation , aided by echocardiography to optimize hemodynamic assessment and management.

The 5All adult patients, admitted directly to participating centers between 2011 and 2019, were extracted from a trauma registry. Two subpopulations were studied: severe hemorrhage (SH) and massive transfusion (MT) groups.A total of 19,396 patients were included, among whom 8.4% (1630) experienced SH and 3% (579) received MT. Within the first 24 hours, 10% received fresh frozen plasma (FFP), rising to 93% and 99% in the subgroups of patients experiencing SH and MT respectively. Only, 8% received fibrinogen concentrate (FC), increasing to 75% and 92% in subgroups SH and MT respectively. Co-administration of FFP and FC became the dominant strategy with 68% of patients at 6 h and 72% at 24 h in SH subgroup. In unadjusted data, mortality was systematically lower in groups that complied with recommendations, a lower mortality than expected was mostly observed in contrast to non-compliant subgroups. The per-patient compliance to studied recommendations was 21% and 22% in SH and MT subgroups.The main hemostatic strategy for major bleeding combined the administration of both FFP and FC, favoring an early additional supply of fibrinogen. Compliance with the recommendations was low in SH and MT subgroups.

Purpose Ultra-protective ventilation with low tidal volume is used in severe acute respiratory distress syndrome (ARDS) patients under extracorporeal membrane oxygenation (ECMO). However, the optimal positive end-expiratory pressure (PEEP) is unknown. The aim of our study was to assess electrical impedance tomography's (EIT) ability to choose the best PEEP for these patients. Materials and methods A recruitment maneuver and after a decremental PEEP trial from 20 to 5 cmH20 were monitored by EIT, with lung images divided into four ventral-to-dorsal horizontal regions of interest. For each patient, three EIT-based PEEP were defined: PEEP ODCLmin (lowest pressure with the least EIT-based collapse lung [CL] and overdistension [OD]), PEEP ODCL15 (lowest pressure able to limit EIT-based collapse to less than or equal to 15% with the least overdistension) and PEEP Comp (PEEP with the highest EIT-based compliance). Results High PEEP levels were significantly associated with more overdistension while decreasing PEEP led to more collapsed zones. PEEP ODCL15 and PEEP Comp were in complete agreement with the reference Pulmonary PEEP (chosen according to usual respiratory clinical and ultrasound criteria), PEEP ODCLmin was in average agreement with the Pulmonary PEEP. Conclusion EIT may be a useful real-time monitoring technique to optimize the PEEP level in severe ARDS patients under ECMO. Take-home message Ultra-protective ventilation with low tidal volume is used in severe acute respiratory distress syndrome patients under extracorporeal membrane oxygenation (ECMO), but the optimal positive end-expiratory pressure is unknown. This trial shows that electrical impedance tomography may be an interesting non-invasive bedside tool to provide real-time monitoring of PEEP impact in severe ARDS patients under ECMO. The Pulmovista® electrical impedance tomography was provided by Drager (Lubeck, Germany) during the study period. Drager had no role in the study design, collection, analysis and interpretation of the data, writing the article, or the decision to submit the article for publication.

Supplemental Digital Content is available in the text., Objectives: Recovery from coma might critically depend on the structural and functional integrity of frontoparietal networks. We aimed to measure this integrity in traumatic brain injury and anoxo-ischemic (cardiac arrest) coma patients by using an original multimodal MRI protocol. Design: Prospective cohort study. Setting: Three Intensive Critical Care Units affiliated to the University in Toulouse (France). Patients: We longitudinally recruited 43 coma patients (Glasgow Coma Scale at the admission < 8; 29 cardiac arrest and 14 traumatic brain injury) and 34 age-matched healthy volunteers. Exclusion criteria were disorders of consciousness lasting more than 30 days and focal brain damage within the explored brain regions. Patient assessments were conducted at least 2 days (5 ± 2 d) after complete withdrawal of sedation. All patients were followed up (Coma Recovery Scale-Revised) 3 months after acute brain injury. Interventions: None. Measurements and Main Results: Functional and structural MRI data were recorded, and the analysis was targeted on the posteromedial cortex, the medial prefrontal cortex, and the cingulum. Univariate analyses and machine learning techniques were used to assess diagnostic and predictive values. Coma patients displayed significantly lower medial prefrontal cortex–posteromedial cortex functional connectivity (area under the curve, 0.94; 95% CI, 0.93–0.95). Cardiac arrest patients showed specific structural disturbances within posteromedial cortex. Significant cingulum architectural disturbances were observed in traumatic brain injury patients. The machine learning medial prefrontal cortex–posteromedial cortex multimodal classifier had a significant predictive value (area under the curve, 0.96; 95% CI, 0.95–0.97), best combination of subregions that discriminates a binary outcome based on Coma Recovery Scale-Revised). Conclusions: This exploratory study suggests that frontoparietal functional disconnections are specifically observed in coma and their structural counterpart provides information about brain injury mechanisms. Multimodal MRI biomarkers of frontoparietal disconnection predict 3-month outcome in our sample. These findings suggest that fronto-parietal disconnection might be particularly relevant for coma outcome prediction and could inspire innovative precision medicine approaches.

Mild thrombocytopenia, changes in platelet gene expression, enhanced platelet functionality, and presence of platelet-rich thrombi in the lung have been associated with thromboinflammatory complications of patients with COVID-19. However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gets internalized by platelets and directly alters their behavior and function in infected patients remains elusive. Here, we investigated platelet parameters and the presence of viral material in platelets from a prospective cohort of 29 patients with severe COVID-19 admitted to an intensive care unit. A combination of specific assays, tandem mass spectrometry, and flow cytometry indicated high levels of protein and lipid platelet activation markers in the plasma from patients with severe COVID-19 associated with an increase of proinflammatory cytokines and leukocyte-platelets interactions. Platelets were partly desensitized, as shown by a significant reduction of αIIbβ3 activation and granule secretion in response to stimulation and a decrease of surface GPVI, whereas plasma from patients with severe COVID-19 potentiated washed healthy platelet aggregation response. Transmission electron microscopy indicated the presence of SARS-CoV-2 particles in a significant fraction of platelets as confirmed by immunogold labeling and immunofluorescence imaging of Spike and nucleocapsid proteins. Compared with platelets from healthy donors or patients with bacterial sepsis, platelets from patients with severe COVID-19 exhibited enlarged intracellular vesicles and autophagolysosomes. They had large LC3-positive structures and increased levels of LC3II with a co-localization of LC3 and Spike, suggesting that platelets can digest SARS-CoV-2 material by xenophagy in critically ill patients. Altogether, these data show that during severe COVID-19, platelets get activated, become partly desensitized, and develop a selective autophagy response.

Background: Diaphragmatic dysfunction is a common condition in intensive care units (ICU). Its presence correlates with prolonged weaning from mechanical ventilation and mortality. Diaphragmatic excursion (EXdi) and thickening fraction (TFdi) are the 2 main measures currently described in diaphragmatic ultrasound, but each has its limitations. Strain and strain rate are already used cardiac sonography and could be of interest in the assessment of diaphragmatic function in ICU. The aim of this work was to evaluate the feasibility of diaphragmatic strain and strain rate in ICU and to describe their distribution, reproducibility and agreement with existing parameters. Methods: All patients who underwent a T-tube weaning test were prospectively included. Ultrasound loops were recorded on each side of the patient during the last 30 minutes of the weaning test. Two operators measured strain, strain rate, EXdi, and TFdi blind to each other in post-treatment analysis. Results: Thirty patients were analyzed. The median values for strain and strain rate were -6.74% and -0.23.s-1 on the left side and -8.17% and -0.22.s-1 on the right side. Concerning strain and strain rate, intra-class coefficients showed systematically a very good reliability between operators. Conclusion: Diaphragmatic strain and strain rate measurements appeared feasible in an ICU environment and seemed reproducible and not strongly correlated with EXdi and TFdi. An improvement of the analysis software is needed to improve the ease of interpretation. The interest of these parameters in clinical practice should be explored in forthcoming studies.

Linezolid is an antibiotic used against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Its primary adverse effect is haematotoxicity. The objective of this study was to analyse the risk factors for onset of thrombocytopenia in critically ill patients treated with linezolid. This was a retrospective, single-centre study of 72 patients. Platelets were measured from D0 to D20 after the start of treatment. The risk factors for thrombocytopenia were identified using a multivariate logistic regression analysis following a Monte Carlo simulation. Following ROC curve analysis, a baseline platelet count lower than 108 × 109/L and a Cmin higher than 4 mg/L, with respective odds ratios of 117 (95% CI [97-206]) and 3 (95% CI [1.5-6.2]) in the simulated population, were identified as risk factors. Among the source population patients combining these 2 factors, a significantly higher number developed thrombocytopenia (66.7% vs. 33.3%, p = 0.0042). A baseline platelet count lower than 108 × 109/L and a Cmin higher than 4 mg/L are risk factors for the onset of thrombocytopenia in critically ill patients treated with linezolid.

The emergence of carbapenemases in gram-negative aerobes is worrying. The aim of this prospective study was to estimate the incidence of acquisition of carbapenem-resistance during treatment in ICU and to identify the risk factors. This was a prospective, observational, cohort study. This study was conducted at intensive care unit, academic medical center, Toulouse Rangueil University Hospital. Patients were included if they received antibiotic treatment with carbapenem for more than 48 h. Biological samples were taken in accordance with current practice in the unit. The main endpoint was the occurrence of bacterial resistance to carbapenems occurring between the onset of treatment and the patient’s exit from the ICU. Uni- and multi-variate analyses were carried out. Of the 364 patients admitted to the unit between May and November 2014, 78 were included in our study and 16 (20.51%) developed resistance. The two main risk factors were a length of stay in ICU of more than 29 days (HR = 3.61, p = 0.01) and the presence of Pseudomonas aeruginosa in the samples taken before the start of treatment (HR = 5.31, p = 0.002). No resistance due to carbapenemase production was observed in this study. The prescription of carbapenems in the ICU setting must adhere to the expert guidelines. In light of our results, special attention must be paid to patients whose stay in intensive care is prolonged, and those in whom Pseudomonas aeruginosa is isolated from bacteriological samples taken before the beginning of antibiotic therapy.

Central venous catheter (CVC) insertion is a common practice for anesthetists, but this invasive procedure generates anxiety and pain in patients that are often underestimated. We compared target-controlled infusion of remifentanil and local lidocaine infiltration with placebo and local lidocaine infiltration to decrease pain scores during CVC placement.We included conscious, adult patients without contraindication to remifentanil or lidocaine. We excluded pregnant women, emergency situations, and opioid abuse. Patients requiring CVC were randomly assigned, using computer-generated allocation numbers stored in sealed envelopes, to receive target-controlled infusion of remifentanil or placebo-all patients received local anesthesia with lidocaine. All patients were hospitalized in a recovery room or intensive care unit, monitored, and received 4 L/min of oxygen.The primary outcome was global pain (Verbal Numeric Rating Pain Scale) during the procedure. Secondary outcomes were pain perceived at every stage of the procedure, anxiety, patient satisfaction, operational ease, and side effects.In this double-blind study, we included 90 patients (split into 2 groups of 45 patients). Global pain was significantly reduced in the remifentanil group: 20 of 100 (95% confidence interval, 16-40) versus 50 of 100 (95% confidence interval, 40-60) in the placebo group; P=0.0009. No major adverse events were observed during this study, and there were no significant differences between both groups regarding side effects.Target-controlled infusion of remifentanil is an effective drug to reduce pain during CVC insertion in association with lidocaine-based local anesthesia, in conscious patients.

In the intensive care unit, patients are subject to discomforts and pain. Their management is essentially based on pharmacologic approaches. Immersive virtual reality could represent an adjunctive non-invasive and non-pharmacological pain control technique. It is based on real-time interaction with an artificial 360° immersive world using interfaces that enable physical and emotional perceptions to make the user feel better trying to reduce pain perception and to limit anxiety. Evaluation of virtual reality in intensive care unit is lacking and further studies are necessary before to introduce this alternative method for critical patients.

Background: The antiviral efficacy of remdesivir is still controversial. We aimed at evaluating its clinical effectiveness in patients with COVID-19 requiring oxygen and/or ventilator support. Methods: In this European multicentre, open-label, parallel-group, randomised, controlled trial in adults hospitalised with COVID-19 (DisCoVeRy, NCT04315948; EudraCT2020-000936-23), participants were randomly allocated to receive usual standard of care alone or in combination with intravenous remdesivir (200 mg on day 1, then 100 mg once-daily for 9 days or until discharge). Treatment assignation was performed via web-based randomisation stratified on illness severity and administrative European region. The primary outcome was the clinical status at day 15 measured by the WHO 7-point ordinal scale, assessed in the intention-to-treat population. Findings: Between March 22nd, 2020 and January 21st, 2021, 857 participants were randomised to one of the two arms in 5 European countries and 832 participants were included for the evaluation of remdesivir (control, n=418; remdesivir, n=414). There was no difference in the clinical status neither at day 15 between treatment groups (OR for remdesivir, 0.98, 95% CI, 0.77 to 1.25, P=0.85) nor at day 29. The proportion of deaths at day 28 was not significantly different between control (8.9%) and remdesivir (8.2%) treatment groups (OR for remdesivir, 0.93 95%CI 0.57 to 1.52, P=0.77). There was also no difference on SARS-CoV-2 viral kinetics (effect of remdesivir on viral load slope, -0.004 log10 cp/10,000 cells/day, 95% CI, -0.03 to 0.02, P=0.75). There was no significant difference in the occurrence of Serious Adverse Events between treatment groups. Interpretation: The use of remdesivir for the treatment of hospitalised patients with COVID-19 was not associated with clinical improvement at day 15 or day 29, nor with a reduction in mortality, nor with a reduction in SARS-CoV-2 RNA. Trial Registration: DisCoVeRy, NCT04315948; EudraCT2020-000936-23 Funding: European Union Commission, French Ministry of Health, DIM One Health Ile-de-France, REACTing, Fonds Erasme-COVID-ULB; Belgian Health Care Knowledge Centre (KCE) Declaration of Interests: Dr. Costagliola reports grants and personal fees from Janssen, personal fees from Gilead, outside the submitted work. Dr. Mentre reports grants from INSERM Reacting (French Government), grants from Ministry of Health (French Government), grants from European Commission, during the conduct of the study; grants from Sanofi, grants from Roche, outside the submitted work. Dr. Hites reports grants from The Belgian Center for Knowledge (KCE), grants from Fonds Erasme-COVID-ULB, during the conduct of the study; personal fees from Gilead, outside the submitted work. Dr. Mootien reports non-financial support from GILEAD, outside the submitted work. Dr. Gaborit reports non-financial support from Gilead, non- financial support from MSD, outside the submitted work. Dr. Botelho-Nevers reports other from Pfizer, other from Janssen, outside the submitted work. Dr. Lacombe reports personal fees and non-financial support from Gilead, personal fees and non-financial support from Janssen, personal fees and non-financial support from MSD, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Abbvie, during the conduct of the study. Dr. Wallet reports personal fees and non-financial support from Jazz pharmaceuticals, personal fees and non-financial support from Novartis, personal fees and nonPage financial support from Kite-Gilead, outside the submitted work. Dr. Kimmoun reports personal fees from Aguettan, personal fees from Aspen, outside the submitted work. Dr. Thiery reports personal fees from AMGEN, outside the submitted work. Dr. Burdet reports personal fees from Da Volterra, personal fees from Mylan Pharmaceuticals, outside the submitted work. Dr. Poissy reports personal fees from Gilead for lectures, outside the submitted work. Dr. Goehringer reports personal fees from Gilead Sciences, non-financial support from Gilead Sciences, grants from Biomerieux, non-financial support from Pfizer, outside the submitted work. Dr. Peytavin reports personal fees from Gilead Sciences, personal fees from Merck France, personal fees from ViiV Healthcare, personal fees from TheraTechnologies, outside the submitted work. Dr. Danion reports personal fees from Gilead, outside the submitted work. Dr. Raffi reports personal fees from Gilead, personal fees from Janssen, personal fees from MSD, personal fees from Abbvie, personal fees from ViiV Healthcare, personal fees from Theratechnologies, personal fees from Pfizer, outside the submitted work. Dr. Gallien reports personal fees from Gilead, personal fees from Pfizer, personal fees from ViiV, personal fees from MSD, outside the submitted work; and has received consulting fee from Gilead in August 2020 to check the registration file of remdesivir for the French administration. Dr. Nseir reports personal fees from MSD, personal fees from Pfizer, personal fees from Gilead, personal fees from Biomerieux, personal fees from BioRad, outside the submitted work. Dr. Lefevre reports personal fees from Mylan, personal fees from Gilead, outside the submitted work. Dr. Guedj reports personal fees from Roche, outside the submitted work. Other authors have nothing to disclose. Ethics Approval Statement: The trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744), and is sponsored by the Institut national de la sante et de la recherche medicale (Inserm, France); it was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included participants (or their legal representatives if unable to consent). The present analysis is based on the protocol v11.0 of December 12th, 2020.

Background: Several studies suggest an increased incidence of thrombosis in COVID-19 patients. However, evidence on how to prevent and even treat it is scarce. The aim of this study was to compare the cumulative incidence of venous thromboembolism (VTE) of two different methods for lower extremity deep vein thrombosis (LE-DVT) diagnosis: systematic vs. clinically guided complete compression venous ultrasonography (CCUS). We conducted a monocentric, prospective, open-label, non-randomized study. All consecutive patients admitted in three intensive care units (ICUs) of University Hospital of Toulouse for COVID-19 pneumonia were included: one performed systematic screening for LE-DVT, the others did not. The primary outcome was the 21-day cumulative incidence of VTE. The secondary end points were the 21-day cumulative incidences of major bleeding and death.Results: Among the 78 patients included, 27 (34.6%) underwent systematic screening for DVT 7 ± 2 days after ICU admission. Thirty-two patients (41.0%) were diagnosed with VTE, with a 21-day cumulative incidence of 42.3% (95% CI, 31.4–55.2), without difference between screened and non-screened patients (hazard ratio 1.45, 95% CI, 0.72–2.93). In the screened group, the frequency of isolated DVT was higher (25.9 vs. 5.9%, p-value = 0.027), but the frequency of pulmonary embolism was not reduced (25.9 vs. 29.4%, p-value = 0.745). The 21-day cumulative incidences of major bleeding and death were 9.6% (95% CI, 4.7–19.2) and 10.3% (95% CI, 5.0–20.8), respectively, without difference between the two groups.Conclusions: A systematic screening for DVT in patients hospitalized in ICU was not associated with a higher diagnosis of VTE or a reduced diagnosis of PE.

During severe sepsis, platelet activation may induce disseminate microvascular thrombosis, which play a key role in critical organ failure. Crucially, most of the studies in this field have explored platelet���leukocyte interactions in animal models, or explored platelets under the spectrum of thrombocytopenia or disseminated intravascular coagulation and have not taken into account the complex interplay that might exist between platelets and leukocytes during human septic shock nor the kinetics of platelet activation. Here, we assessed platelet activation parameters at the admission of patients with sepsis to the intensive care unit (ICU) and 48 hours later. Twenty-two patients were enrolled in the study, thirteen (59.1%) of whom were thrombocytopenic. The control group was composed of twelve infection-free patients admitted during the study period. The activation parameters studied included platelet-leukocyte interactions, assessed by flow cytometry in whole blood, as well as membrane surface and soluble platelet activation markers measured by flow cytometry and dedicated ELISA kits. We also investigated platelet aggregation and secretion responses of patients with sepsis following stimulation, compared to controls. At admission, the level of circulating monocyte-platelet and neutrophil-platelet heterotypic aggregates was significantly higher in sepsis patients compared to controls and returned to a level comparable to controls or even below 48 hours later. Basal levels of CD62P and CD63 platelet membrane exposure at admission and 48 hours later were low and similar to controls. In contrast, plasma level of soluble GPVI and soluble CD40 ligand was significantly increased in septic patients, at the two times of analysis, reflecting previous platelet activation. Platelet aggregation and secretion responses induced by specific agonists were significantly decreased in septic conditions, particularly 48 hours after admission. Hence, we have observed for the first time that critically ill septic patients compared to controls have both an early and durable platelet activation while their circulating platelets are less responsive to different agonists.

Recent European Society of Parenteral and Enteral Nutrition guidelines highlighted the interest of prevention, diagnosis and treatment of malnutrition in the management of coronavirus disease 19 (COVID-19) patients. The aim of our study was to evaluate the prevalence of malnutrition in patients hospitalised for COVID-19. In a prospective observational cohort study malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition (GLIM) two-step approach. Patients were divided into two groups according to the diagnosis of malnutrition. Covariate selection for the multivariate analysis was based on P n 46, 57·5 %) was similar in the two groups. Three patients who died (3·75 %) were malnourished. Multivariate analysis exhibited that low BMI (OR 0·83, 95 % CI 0·73, 0·96, P = 0·0083), dyslipidaemia (OR 29·45, 95 % CI 3·12, 277·73, P = 0·0031), oral intake reduction P = 0·0422) and glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration; CKD-EPI) at admission (OR 0·979, 95 % CI 0·96, 0·998, P = 0·0297) were associated with the occurrence of malnutrition. We demonstrate the existence of a high prevalence of malnutrition in a general cohort of COVID-19 inpatients according to GLIM criteria. Nutritional support in COVID-19 care seems an essential element.

Background To compare patients hospitalised in the intensive care unit (ICU) after surgery for community-acquired intra-abdominal infection (CA-IAI) and hospital-acquired intra-abdominal infection (HA-IAI) in terms of mortality, severity and complications. Methods Retrospective study including all patients admitted to 2 ICUs within 48 h of undergoing surgery for peritonitis. Results Two hundred twenty-six patients were enrolled during the study period. Patients with CA-IAI had an increased 28-day mortality rate compared to those with HA-IAI (30% vs 15%, respectively (p = 0.009)). At 90 days, the mortality rates were 36.7 and 37.5% in the CA-IAI group and HA-IAI group, respectively, with a similar APACHE II score on admission (median: 21 [15–25] vs. 21 [15–24] respectively, p = 0.63). The patients with HA-IAI had prolonged ICU and hospital stays (median: 17 [7–36] vs. 6[3–12] days, p p = 0.001), and experienced more complications (reoperation and reintubation) than those with CA-IAI. Conclusion CA-IAI group had higher 28-day mortality rate than HA-IAI group. Mortality was similar at 90 days but those with HA-IAI had a prolonged ICU and hospital stay. In addition, they developed more complications.

BACKGROUND The effects of SARS-CoV-2 (COVID-19) on the myocardium and their role in the clinical course of infected patients are still unknown. The severity of SARS-CoV-2 is driven by hyperinflammation, and the effects of SARS-CoV-2 on the myocardium may be significant. This study proposes to use bedside observations and biomarkers to characterize the association of COVID-19 with myocardial injury. OBJECTIVE The aim of the study is to describe the myocardial function and its evolution over time in patients infected with SARS-CoV-2 and to investigate the link between inflammation and cardiac injury. METHODS This prospective, monocentric, observational study enrolled 150 patients with suspected or confirmed SARS-CoV-2 infection at Toulouse University Hospital, Toulouse, France. Patients admitted to the intensive care unit (ICU), regular cardiologic ward, and geriatric ward of our tertiary university hospital were included during the pandemic period. Blood sampling, electrocardiography, echocardiography, and morphometric and demographic data were prospectively collected. RESULTS A total of 100 patients were included. The final enrolment day was March 31, 2020, with first report of results at the end of the first quarter of 2021. The first echocardiographic results at admission of 31 patients of the COCARDE-ICU substudy population show that biological myocardial injury in COVID-19 has low functional impact on left ventricular systolic function. CONCLUSIONS A better understanding of the effects of COVID-19 on myocardial function and its link with inflammation would improve patient follow-up and care. CLINICALTRIAL Clinicaltrials.gov NCT04358952; https://clinicaltrials.gov/ct2/show/NCT04358952 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/24931

International audience; Purpose: The 4-point score is the corner stone of brain death (BD) confirmation using computed tomography angiography (CTA). We hypothesized that considering the superior petrosal veins (SPVs) may improve CTA diagnosis performance in BD setting. We aimed at comparing the diagnosis performance of three revised CTA scores including SPVs and the 4-point score in the confirmation of BD.Methods: In this retrospective study, 69 consecutive adult-patients admitted in a French University Hospital meeting clinical brain death criteria and receiving at least one CTA were included. CTA images were reviewed by two blinded neuroradiologists. A first analysis compared the 4-point score, considered as the reference and three non-opacification scores: a "Toulouse score" including SPVs and middle cerebral arteries, a "venous score" including SPVs and internal cerebral veins and a "7-score" including all these vessels and the basilar artery. Psychometric tools, observer agreement and misclassification rates were assessed. A second analysis considered clinical examination as the reference.Results: Brain death was confirmed by the 4-score in 59 cases (89.4 %). When compared to the 4-score, the Toulouse score displayed a 100 % positive predictive value, a substantial observer agreement (0.77 [0.53; 1]) and the least misclassification rate (3.03 %). Results were similar in the craniectomy subgroup. The Toulouse score was the only revised test that combined a sensitivity close to that of the 4-score (86.4 % [75.7; 93.6] and 89.4 % [79.4; 95.6], p-value < 0.001, respectively) and a substantial observer agreement.Conclusions: A score including SPVs and middle cerebral arteries is a valid method for BD confirmation using CTA even in patients receiving craniectomy.

BackgroundTo explore risk factors for unfavorable outcome (death or requiring invasive mechanical ventilation at 28 days from ICU admission) of critically ill COVID-19 patients hospitalized in the Toulouse regionMethodsRetrospective cohort of critically ill COVID-19 patients sequentially admitted to 12 ICUs in Toulouse region (March 9, 2020, to April 8, 2020). All patients had laboratory confirmed SARS-CoV-2 infection and required invasive mechanical ventilation. Baseline characteristics, pathophysiological respiratory data, clinical outcomes, viral shredding, and chest CT scan were collected.ResultsA total of 150 patients were included (median age, 68 years (interquartile range, (IQR), 58-72; 81% male). The most common comorbidities were hypertension (77, 51%) and obesity (42, 28%). At ICU admission, the median PaO2/FiO2 ratio was 138 (IQR,112-178). During hospitalization, the rate of ventilator-acquired pneumonia (VAP) was 61% and 51 (34%) patients had acute kidney injury (AKI) with a Kidney Disease Improving Global Outcomes (KDIGO) score > 1. The 28-day mortality was 15.3%, and 50 (33%) patients had unfavorable outcome. We found that VAP (5.91; 2.10-10.03; p value = 0.002) and AKI with a KDIGO score > 1 (4.71; 1.69-14.41; p value = 0.004) were associated with increased odds of unfavorable outcome. Neither, chest CT scan data on admission, nor pathophysiological respiratory data during ICU stay were associated to patient’s outcome.ConclusionThe potential risk factors of AKI and VAP could help clinicians to identify patients with poor prognosis at an early stage. Targeted care of these factors might have a significant impact on COVID-19 patient’s outcome.

Background: Recent ESPEN guidelines highlighted the interest of prevention, diagnosis and treatment of malnutrition in the management of coronavirus disease 19 (COVID-19) patients. The aim of our study was to evaluate the prevalence of malnutrition in patients hospitalized for COVID-19. Methods: Prospective observational cohort study on COVID-19 inpatients admitted to a tertiary hospital. Malnutrition was diagnosed according to the Global Leadership Initiative on Malnutrition two-step approach. Patients were divided in two groups according to the diagnosis of malnutrition. Covariate selection for the multivariate analysis was based on P value Results: 80 patients were prospectively enrolled in the study. Thirty patients (37.5%) had criteria for malnutrition. The need for ICU admission (n=46, 57.5%) was similar in the two groups. Three patients who died (3.75%) were malnourished. Multivariate analysis exhibited that low BMI (OR=0.83, 95% CI [0.73-0.96], p=0.0083), dyslipidemia (OR=29.45, 95% CI [3.12-277.73], p=0.0031), oral intakes reduction Conclusions: We demonstrate the existence of a high prevalence of malnutrition (37.5%) in a general cohort of COVID-19 inpatients according to GLIM criteria. Considering this high prevalence, nutritional support in COVID-19 care seems an essential element. Trial registration: Ethical Committee No 2020-A01237-32)(RC31/20/0165 NUTRI-COV

Biological cardiac injury related to the Severe Acute Respiratory Syndrome Coronavirus-2 infection has been associated with excess mortality. However, its functional impact remains unknown. The aim of our study was to explore the impact of biological cardiac injury on myocardial functions in patients with COVID-19. 31 patients with confirmed COVID-19 (CoV+) and 16 controls (CoV−) were prospectively included in this observational study. Demographic data, laboratory findings, comorbidities, treatments and myocardial function assessed by transthoracic echocardiography were collected and analysed in CoV+ with (TnT+) and without (TnT−) elevation of troponin T levels and compared with CoV−. Among CoV+, 13 (42%) exhibited myocardial injury. CoV+/TnT + patients were older, had lower diastolic arterial pressure and were more likely to have hypertension and chronic renal failure compared with CoV+/TnT−. The control group was comparable except for an absence of biological inflammatory syndrome. Left ventricular ejection fraction and global longitudinal strain were not different among the three groups. There was a trend of decreased myocardial work and increased peak systolic tricuspid annular velocity between the CoV− and CoV + patients, which became significant when comparing CoV− and CoV+/TnT+ (2167 ± 359 vs. 1774 ± 521%/mmHg, P = 0.047 and 14 ± 3 vs. 16 ± 3 cm/s, P = 0.037, respectively). There was a decrease of global work efficiency from CoV− (96 ± 2%) to CoV+/TnT− (94 ± 4%) and then CoV+/TnT+ (93 ± 3%, P = 0.042). In conclusion, biological myocardial injury in COVID 19 has low functional impact on left ventricular systolic function.

BackgroundIn sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. VE-cadherin, an adherens junction protein, is the gatekeeper of endothelial cohesion. Kinins, released during sepsis, induce vascular leakage and vasodilation. They act via two G-protein coupled receptors: B1 (B1R) and B2 (B2R). B1R is inducible in the presence of pro-inflammatory cytokines, endotoxins or after tissue injury. It acts at a later stage of sepsis and elicits a sustained inflammatory response. The aim of our study was to investigate the relationships between B1R and VE-cadherin destabilization in vivo in a later phase of sepsis.MethodsExperimental, prospective study in a university research laboratory. We used a polymicrobial model of septic shock by cecal ligation and puncture in C57BL6 male mice or C57BL6 male mice that received a specific B1R antagonist (R-954). We studied the influence of B1R on sepsis-induced vascular permeability 30 h after surgery for several organs, and VE-cadherin expression in the lung and kidneys by injecting R-954 just before surgery. The 96-h survival was determined in mice without treatment or in animals receiving R-954 as a “prophylactic” regimen (a subcutaneous injection of 200 µg/kg, prior to CLP and 24 h after CLP), or as a “curative” regimen (injection of 100 µg/kg at H6, H24 and H48 post-surgery).ResultsB1R inactivation helps to maintain MAP above 65 mmHg but induces different permeability profiles depending on whether or not organ perfusion is autoregulated. In our model, VE-cadherin was destabilized in vivo during septic shock. At a late stage of sepsis, the B1R blockade reduced the VE-cadherin disruption by limiting eNOS activation. The survival rate for mice that received R-954 after sepsis induction was higher than in animals that received an antagonist as a prophylactic treatment.ConclusionsB1R antagonizing reduced mortality in our model of murine septic shock by limiting the vascular permeability induced by VE-cadherin destabilization through maintenance of the macrohemodynamics, consequently limiting organ dysfunctions.

Interprofessional simulation (IPS) training is an effective way to learn crisis resource management. The type of debriefing used in IPS training may affect participants' performance and their level of psychological safety. We aimed to assess and compare performance after standard collective debriefing versus a combination of individual and collective debriefing ("combined" approach).Randomized, controlled multicenter trial. IPS sessions were randomized to have either standard or combined debriefing. Each team's performance in the IPS session was assessed with the Team Emergency Assessment Measure. The participants assessed the debriefing quality with the Debriefing Assessment for Simulation in Healthcare.Forty IPS sessions were randomized, and 30 were analyzed, 15 using standard collective debriefing and 15 the combined individual-collective method. Teams' performance improved with both types of debriefing, based on pre-post testing (P.01), and there were no significant differences in overall performance scores between the 2 types of debriefing (P=.64). However, the combined approach was associated with higher scores for leadership skills (P.05) and psychological safety, and the participants' learning experience was better (P.05).During IPS courses on crisis resource management, debriefing improves participants' performance, but similar overall results can be obtained with both debriefing methods. Combined debriefing might be more effective for improving participants' leadership skills and psychological safety and also provide a better learning experience.La simulación interprofesional (SIP) es eficaz para aprender gestión de recursos de crisis. La modalidad de debriefing utilizada en la SIP puede influir en el rendimiento de los participantes y en su integridad psicológica. Se evalúa y compara el rendimiento de un debriefing estándar (DE) –colectivo– con un debriefing combinado (DC) –individual y colectivo– en cursos de SIP en escenarios que simulan pacientes con patología aguda y grave.Ensayo controlado, aleatorizado y multicéntrico. Se aleatorizó el tipo de debriefing realizado (DE o DC) en las sesiones de SIP. El rendimiento del debriefing se evaluó con la escala TEAM (Team Emergency Assessment Measure). La calidad de la SIP fue valorada por los participantes con la escala DASH (Debriefing Assessment for Simulation in Healthcare©).Se aleatorizaron 40 cursos de SIP de los que se analizaron 30. Quince realizaron DE y 15 DC. Ambos grupos mejoraron entre la pre y la posprueba (p0,01), pero no hubo diferencias en el rendimiento global entre ambas modalidades de debriefing (p = 0,64). El DC obtuvo mejores resultados que el DE en la capacidad de liderazgo (p0,05), en la percepción de seguridad psicológica y en la experiencia de aprendizaje eficaz (p0,05).Durante la SIP en situaciones de crisis, el debriefing mejora el rendimiento de los participantes, sin diferencias entre un DE y un DC. El DC podría ser más efectivo para mejorar la capacidad de liderazgo, la seguridad psicológica y la experiencia del aprendizaje.

Platelets are mainly known for their key role in hemostasis and thrombosis. However, studies over the last two decades have shown their strong implication in mechanisms associated with inflammation, thrombosis, and the immune system in various neoplastic, inflammatory, autoimmune, and infectious diseases. During sepsis, platelets amplify the recruitment and activation of innate immune cells at the site of infection and contribute to the elimination of pathogens. In certain conditions, these mechanisms can lead to thromboinflammation resulting in severe organ dysfunction. Here, we discuss the interactions of platelets with leukocytes, neutrophil extracellular traps (NETs), and endothelial cells during sepsis. The intrinsic properties of platelets that generate an inflammatory signal through the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome are discussed. As an example of immunothrombosis, the implication of platelets in vaccine-induced immune thrombotic thrombocytopenia is documented. Finally, we discuss the role of megakaryocytes (MKs) in thromboinflammation and their adaptive responses.

Sepsis is associated with thrombocytopenia and microvascular thrombosis. Studies have described platelets implication in this pathology but their kinetics of activation and behavior remain poorly known. We show in a mouse model of peritonitis, the appearance of platelet-rich thrombi in organ microvessels and organ damage. Complementary methods are necessary to characterize platelet activation during sepsis as circulating soluble markers and platelet-monocyte aggregates revealed early platelet activation, while surface activation markers were detected at later stage. A microfluidic based ex-vivo thrombosis assay demonstrated that platelets from septic mice have a prothrombotic behavior at shear rate encountered in microvessels. Interestingly, we found that even though phosphoinositide-3-kinase β−deficient platelet mice formed less thrombi in liver microcirculation, peritoneal sepsis activates a platelet alternative pathway to compensate the otherwise mandatory role of this lipid-kinase to form stable thrombi at high shear rate. Platelets are rapidly activated during sepsis. Thrombocytopenia can be attributed in part to platelet-rich thrombi formation in capillaries and platelet-leukocytes interactions. Platelets from septic mice have a prothrombotic phenotype at a shear rate encountered in arterioles. Further studies are necessary to unravel molecular mechanisms leading to this prothrombotic state of platelets in order to guide the development of future treatments of polymicrobial sepsis.

Background The effects of SARS-CoV-2 (COVID-19) on the myocardium and their role in the clinical course of infected patients are still unknown. The severity of SARS-CoV-2 is driven by hyperinflammation, and the effects of SARS-CoV-2 on the myocardium may be significant. This study proposes to use bedside observations and biomarkers to characterize the association of COVID-19 with myocardial injury. Objective The aim of the study is to describe the myocardial function and its evolution over time in patients infected with SARS-CoV-2 and to investigate the link between inflammation and cardiac injury. Methods This prospective, monocentric, observational study enrolled 150 patients with suspected or confirmed SARS-CoV-2 infection at Toulouse University Hospital, Toulouse, France. Patients admitted to the intensive care unit (ICU), regular cardiologic ward, and geriatric ward of our tertiary university hospital were included during the pandemic period. Blood sampling, electrocardiography, echocardiography, and morphometric and demographic data were prospectively collected. Results A total of 100 patients were included. The final enrolment day was March 31, 2020, with first report of results at the end of the first quarter of 2021. The first echocardiographic results at admission of 31 patients of the COCARDE-ICU substudy population show that biological myocardial injury in COVID-19 has low functional impact on left ventricular systolic function. Conclusions A better understanding of the effects of COVID-19 on myocardial function and its link with inflammation would improve patient follow-up and care. Trial Registration Clinicaltrials.gov NCT04358952; https://clinicaltrials.gov/ct2/show/NCT04358952 International Registered Report Identifier (IRRID) DERR1-10.2196/24931