Emmanuel Besnier

Background: Hypertonic sodium lactate (HSL) has demonstrated beneficial effects in experimental sepsis, improving hemodynamics, modulating inflammation, and supporting cellular metabolism. Nevertheless, prior studies have not specifically addressed microcirculation, despite its critical impairment during sepsis and the absence of targeted therapies. We evaluated the therapeutic effects of HSL in a in vivo resuscitated rat model (Male wistars) of cecal ligation and puncture (CLP), with a particular focus on microcirculatory function, followed by ex vivo investigation of sodium lactate on vascular reactivity. Results: 10 h after CLP rats were infused with 0.9% NaCl or 11.2% HSL for 18 h before exploration. No difference was observed on arterial pressure, echocardiography and pressure-volume loops. HSL improved mesenteric perfusion (1126 [923–1300] vs. 816.5 [692–919] Perfusion Unit, p = 0.012) and TNF-α plasma levels (26.2 [22.8–37.1] vs. 42.6 [32.6–47.3] pg/mL, p = 0.001). Ex vivo, mesenteric artery reactivity experiments from healthy rats was tested with or without LPS-stimulation and glucose deprivation. Lactate dose-dependently restored LPS-impaired vasoconstriction, showing an independent effect on small arteries. In glucose deprivation conditions, HSL was able to restore vascular reactivity in normal or LPS-stimulated arteries. Conclusions: HSL specifically improved microcirculation and reduced systemic inflammation in septic rats. Moreover, lactate may act as an alternative to glucose in deprivation conditions. These benefits support its translational potential as a resuscitation fluid in sepsis.

Introduction: Vasoplegic syndrome (VS) is a severe complication after cardiac surgery with cardiopulmonary bypass (CPB), characterised by vasodilation, hypotension and vasopressor dependence. Endothelial dysfunction, dysregulated nitric oxide signalling, inflammation and glycocalyx injury may contribute. Combining flow-mediated dilation (FMD), sublingual side-stream dark-field (SDF) imaging and biomarkers may improve postoperative vascular phenotyping. The primary objective is to compare allometrically corrected brachial artery FMD between patients with VS and patients without VS 48 hours after CPB weaning. Methods and analysis: This prospective, single-centre observational cohort study will enrol 124 adults aged 18–80 years undergoing cardiac surgery with CPB (62 VS and 62 non-VS). VS is defined clinically as norepinephrine bitartrate ≥0.05 µg/kg/min for at least 4 hours to maintain mean arterial pressure ≥65 mm Hg after CPB weaning, following haemodynamic optimisation and exclusion of a predominant low-cardiac-output phenotype or another cause of shock. FMD, SDF imaging and biomarkers will be assessed at 4–8 and 48 hours after CPB weaning. The primary comparison will use multiple linear regression for corrected FMD at 48 hours with prespecified covariate adjustment. Secondary and exploratory analyses will assess SDF-derived parameters, biomarkers and associations across modalities. Ethics and dissemination: The protocol was approved by the Comité de Protection des Personnes Sud-Méditerranée III (CPP Sud-Méditerranée III; 2023-A02079-36). For this non-interventional routine-care study, French law requires prior oral and written information and absence of opposition rather than written consent; absence of opposition will be documented. Results will be published in peer-reviewed journals and presented at scientific conferences. Trial registration number: NCT06318689 .

Le sepsis concerne des millions de patients dans le monde et engendre une mortalité importante. La pénétration de l’agent pathogène est responsable d’un ensemble de réactions de l’hôte, avec une altération de grandes fonctions de l’organisme pouvant conduire à la défaillance d’organe. L’endothélium est un élément majeur du système cardiovasculaire assurant notamment la perfusion tissulaire et la régulation des flux hydrosodés entre les secteurs vasculaire et interstitiel. Au cours du sepsis une altération de cet endothélium peut survenir et induire un défaut de microcirculation et une fuite capillaire par altération de la fonction barrière, conduisant à l’hypoxie cellulaire et au syndrome oedémateux.Ce travail de doctorat se divise en une approche clinique évaluant l’effet du syndrome oedémateux sur le pronostic des patients de réanimation, et une approche expérimentale évaluant les effets de nouvelles thérapies sur cet aspect de la fonction endothéliale.Dans la première partie, nous avons identifié que la balance hydrique positive (entrées – sorties de fluides) était associée à la mortalité de patients critiques admis pour assistance circulatoire par ExtraCorporeal Membrane Oxygenation (ECMO) veino-artérielle dans le cadre d’un choc cardiogénique réfractaire. Ceci confirmait des résultats précédents chez les patients septiques et illustrait que ce phénomène concernait également des patients critiques non septiques.Dans la deuxième partie, nous avons évalué dans un premier temps l’effet d’un anticorps anti-VEGF, le bevacizumab, dans un modèle de sepsis par ponction ligature caecale chez la souris. Le VEGF est impliqué dans les phénomènes de fuite paracellulaire et des auteurs avaient préalablement montré un effet bénéfique du bevacizumab sur la fuite capillaire dans le sepsis. Nous n’avons retrouvé aucune modification de la mortalité, malgré un effectif conséquent (n>50), ne justifiant pas la poursuite des investigations. Nous avons ensuite évalué les effets du lactate de sodium molaire (LSM), fluide hypertonique et énergétique ayant suggéré récemment un effet bénéfique sur la macro et la microcirculation dans un modèle endotoxinique, avec notamment une réduction de la balance hydrique. A cette fin nous avons réalisé un modèle de sepsis chez le rat. L’administration continue de LSM induisait une amélioration de la perfusion tissulaire intestinale (microcirculation) et réduisait la fuite capillaire dans l’intestin, le poumon et le foie en comparaison avec le NaCl 0,9%. De plus le LSM réduisait l’inflammation (IL-1b, TNFa, IL-10) et les taux de VEGF-A, et améliorait la fonction cardiaque (echocardiographie : débit cardiaque, fraction de raccourcissement ; cathétérisme cardiaque gauche : pente maximale systolique et compliance ventriculaire). La perfusion de LSM induisait une augmentation de la lactatémie et de la pyruvatémie sans modification du ratio, témoin de la métabolisation du lactate perfusé, avec augmentation de la glycémie (néoglucogenèse) et de l’hydroxybutyrate, suggérant fortement un effet métabolique de sa perfusion.Ainsi le LSM pourrait être un fluide novateur au cours du sepsis et nécessite d’être évalué au cours d’essais cliniques chez l’Homme

Introduction Postoperative pulmonary complications (PPCs) are common after cardiac surgery and are associated with significant morbidity and mortality. Lung-protective ventilation strategies have been proposed to reduce PPCs, but the optimal level of positive end-expiratory pressure (PEEP) and the use of alveolar recruitment manoeuvres (RMs) remain controversial. Methods/analysis In this investigator-initiated, multicentre, open, randomised, parallel-group, superiority clinical trial, elective cardiac surgery patients at risk of PPCs will be assigned to one of two intraoperative ventilation strategies: (1) an open-lung ventilation strategy with protective ventilation, moderate PEEP and RMs or (2) a standard protective ventilation with low PEEP and no RM. The primary outcome will be a composite of prolonged (>24 hour) postoperative mechanical ventilation, reintubation for any cause or hospital-acquired pneumonia within 7 days of surgery, or death within 28 days of surgery. Data will be analysed on an intention-to-treat basis. Ethics and dissemination The VACARM (impact of intraoperatiVe moderAte positive end-expiratory pressure with reCruitment mAnoeuvres versus low positive end-expiRatory pressure on major postoperative pulMonary complications and death after on-pump cardiac surgery in high-risk patients) trial has been approved by an independent ethics committee for all study centres. Recruitment began in July 2021. Results will be published in international peer-reviewed medical journals. Trial registration number ClinicalTrials.gov NCT04408495.

Background/Objectives: Rapid sequence induction (RSI) for the prevention of aspiration is a frequent clinical situation during anesthesia. The lack of international guidelines on this topic may lead to differences in practices. The aim of this survey is to identify the clinical practices in RSI among practitioners at an international level. Methods: International declarative survey across the ESAIC network. Results: A total of 491 respondents in 61 countries, 74% of them were seniors and 42% with over 20 years of experience. Most of the practitioners (87%) performed preoxygenation under a high flow of oxygen (>10 L/min) with no PEEP and no pressure support and 69% use opioids in most cases of RSI. The Sellick maneuver was used by 42% of respondents. RSI was used in most situations at high risk of aspiration (bowel obstruction, trauma within 6 h after the last meal, caesarian section). RSI was used in 53% of cases of appendicectomy in the absence of vomiting. Conversely, 29% did not use RSI in cases of symptomatic esophageal reflux. A total of 11% encountered at least one episode of grade IV anaphylaxis to succinylcholine or rocuronium and 24% aspiration pneumonia. Conclusions: Our results support the need for international guidelines on RSI to limit differences between practitioners and countries.

Introduction: Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery. We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery. Methods and analysis: Multicentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea–vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay. Ethics and dissemination: This trial has been approved by an independent ethics committee ( Comité de Protection des Personnes Ouest III–Angers on 23 February 2021). Results will be submitted in international journals for peer reviewing. Trial registration number: NCT04940689 , EudraCT 2020-002126-90.