Continuation vs Discontinuation of Renin-Angiotensin System Inhibitors Before Major Noncardiac Surgery

ImportanceBefore surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.ObjectiveTo evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, setting, and participantsRandomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.InterventionPatients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main outcomes and measuresThe primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.ResultsOf the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and relevanceAmong patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial registrationClinicalTrials.gov Identifier: NCT03374449

Microglial activation : mechanisms and long term consequences

La neuro-inflammation induite par l'inflammation systémique ou générée en réponse à une lésion cérébrale aiguë a des conséquences cliniques néfastes : elle est mise en cause dans l'aggravation des lésions cérébrales aiguës chez l'homme, aussi bien chez l'adulte que chez l'enfant. La microglie est l'effecteur cérébral principal de cette réponse inflammatoire, et peut présenter selon les situations un profil neurotoxique ou, au contraire, anti-inflammatoire et régulateur. La compréhension des mécanismes d'activation microgliale et de leurs conséquences est capitale pour une meilleure prise en charge des malades. La première partie de ce travail de thèse s'intéresse aux conséquences de l'inflammation néonatale associée à la prématurité sur la réponse microgliale à l'âge adulte, face à de nouvelles agressions cérébrales que sont l'inflammation systémique et les lésions cérébrales aiguës. Dans un modèle murin d'inflammation néonatale, nous avons mis en évidence d'importantes modifications du transcriptome microglial une fois ces souris adultes. De plus, un stimulus inflammatoire à l'âge adulte modifie le profil d'activation microgliale, le pic des marqueurs pro-inflammatoires et immuno-régulateurs survenant plus précocement et intensément, démontrant l'existence d'une mémoire du système immunitaire inné cérébral. Ces modifications dans le profil d'activation microgliale s'accompagnent dans un modèle de lésion cérébrale excitotoxique d'une majoration de la taille des lésions de la substance blanche. Un traitement par mélatonine des souriceaux prévient cette aggravation. La deuxième partie de ce travail a consisté à caractériser in vitro le profil d'activation microgliale en réponse à une stimulation par HMGB1, une alarmine relarguée lors de la mort cellulaire et donc présente en cas de lésion cérébrale aiguë mais aussi de lésions extra-crâniennes associées. Nous avons montré que le profil d'activation microgliale dépend du type d'HMGB1 utilisé. Les microglies exposées à la forme recombinante de chez Sigma présentent un profil transcriptomique proinflammatoire mais une baisse des taux de cytokines sécrétées dans le milieu. Ces résultats mettent en évidence l'importance de l'inflammation et de l'activation microgliale dans le pronostic des lésions cérébrales et offrent la possibilité de mettre en place des stratégies neuroprotectrices innovantesNeuroinflammation induced by systemic inflammation or generated in response to acute brain injury has adverse clinical consequences: it is implicated in exacerbation of acute brain injury in humans, for adults as well as for children. Microglia is the main effector of this cerebral inflammatory response, and may present, depending on the situation, a neurotoxic or - on the opposite - anti-inflammatory and regulating profile. To decipher the mechanisms of microglial activation and their consequences is essential for better management of patients.The first part of this thesis focuses on the consequences of neonatal inflammation associated with prematurity on the microglial response in adulthood, in case of new cerebral aggressions such as systemic inflammation or acute brain injury. Relying on a mouse model of inflammation of the preterm infant, we have demonstrated drastic modifications of the microglial transcriptome once these mice are adults. Moreover, when an inflammatory stimulus occurs in adulthood, the microglial activation profile is altered, the peak of pro-inflammatory and immuno-regulatory markers occurring earlier, demonstrating the existence of a memory of the cerebral innate immune system. These changes in the microglial activation profile are accompanied in a model of excitotoxic brain injury by an increase of the white matter lesion size. Melatonin treatment of mice prevents the happening of this worse outcome. In the second part of this thesis, we characterized the microglial activation profile in vitro, in response to stimulation by HMGB1, a damage associated molecular pattern released during cell death and therefore present in acute brain injuries but also in associated extra-cranial injuries. We have shown that the microglial activation profile depends of the kind of HMGB1 used. Microglia exposed to Sigma recombinant form have a proinflammatory transcriptomic profile but a lower release of cytokines in the culture medium. These results highlight the importance of inflammation and microglial activation in the prognosis of brain injuries and offer the opportunity to implement innovative neuroprotective strategie

Brain damage of the preterm infant:new insights into the role of inflammation

Epidemiological studies have shown a strong association between perinatal infection/inflammation and brain damage in preterm infants and/or neurological handicap in survivors. Experimental studies have shown a causal effect of infection/inflammation on perinatal brain damage. Infection including inflammatory factors can disrupt programmes of brain development and, in particular, induce death and/or blockade of oligodendrocyte maturation, leading to myelin defects. Alternatively, in the so-called multiple-hit hypothesis, infection/inflammation can act as predisposing factors, making the brain more susceptible to a second stress (sensitization process), such as hypoxic–ischaemic or excitotoxic insults. Epidemiological data also suggest that perinatal exposure to inflammatory factors could predispose to long-term diseases including psychiatric disorders.</jats:p

A communication strategy based on Twitter improves article citation rate and impact factor of medical journals

International audienc

Les missions et objectifs du Réseau recherche de la Société française d’anesthésie et de réanimation

National audienceDepuis une dizaine d’années, la recherche clinique en Anesthésie-Réanimation voit une augmentation du nombre de protocoles développés et de publications, tant au niveau médical que paramédical. Des réseaux très structurés existent à l’étranger et imposent une concurrence importante dans la course à l’innovation, ainsi qu’au déroulement et à la valorisation des protocoles de recherche. La complexification récente de la méthodologie de la recherche clinique rend la professionnalisation et la structuration de la recherche clinique au sein de notre société savante nécessaires. Le Comité Réseau Recherche de la Société française d’anesthésie et de réanimation (SFAR) a pour but de fournir un label qualité à la recherche clinique médicale et paramédicale, grâce à un accompagnement des projets de recherche tout au long du processus : expertise et interaction avec les investigateurs, recrutement des centres, suivi du déroulement des études, aide à la rédaction des articles. Les objectifs sont d’aider les investigateurs à optimiser les chances de financements de projets, d’assurer la faisabilité des travaux et de valoriser scientifiquement les résultats. Pour la SFAR, cette valorisation des travaux de recherche nationaux participe au rayonnement international de notre spécialité

SARS-CoV-2 vaccination efficacy on hospitalisation and variants

International audienceWe report data regarding three countries with similar healthcare systems which had three different vaccinal strategies between 1st of January and 10th of April 2021: rapid full vaccination (Israel), rapid first-dose vaccination (United Kingdom) and a delayed vaccination strategy (France)

Melatonin for prevention of postoperative delirium after lower limb fracture surgery in elderly patients (DELIRLESS): study protocol for a multicentre randomised controlled trial

International audienceIntroductionPostoperative delirium (POD) is one of the most frequent complication after surgery in elderly patients, and is associated with increased morbidity and mortality, prolonged length of stay, cognitive and functional decline leading to loss of autonomy, and important additional healthcare costs. Perioperative inflammatory stress is a key element in POD genesis. Melatonin exhibits antioxidative and immune-modulatory proprieties that are promising concerning delirium prevention, but in perioperative context literature are scarce and conflicting. We hypothesise that perioperative melatonin can reduce the incidence of POD.Methods and analysisThe DELIRLESS trial is a prospective, national multicentric, phase III, superiority, comparative randomised (1:1) double-blind clinical trial. Among patients aged 70 or older, hospitalised and scheduled for surgery of a severe fracture of a lower limb, 718 will be randomly allocated to receive either melatonin 4 mg per os or placebo, every night from anaesthesiologist preoperative consultation and up to 5 days after surgery. The primary outcome is POD incidence measured by either the French validated translation of the Confusion Assessment Method (CAM) score for patients hospitalised in surgery, or CAM-ICU score for patients hospitalised in ICU (Intensive Care Unit). Daily delirium assessment will take place during 10 days after surgery, or until the end of hospital stay if it is shorter. POD cumulative incidence function will be compared at day 10 between the two randomised arms in a competing risks framework, using the Fine and Grey model with death as a competing risk of delirium.Ethics and disseminationThe DELIRLESS trial has been approved by an independent ethics committee the Comité de Protection des Personnes (CPP) Sud-Est (ref CPP2020-18-99 2019-003210-14) for all study centres. Participant recruitment begins in December 2020. Results will be published in international peer-reviewed medical journals.Trial registration number NCT04335968, first posted 7 April 2020