Philippe Guerci

Effets de thérapies actuelles et nouvelles sur la microcirculation sévèrement endommagée: Au cours des 20 dernières années, la microcirculation a été considérée comme la pierre angulaire du développement de la défaillance d’organe chez les patients critiques. De toute évidence, la microcirculation est devenue une cible thérapeutique. En raison de la complexité de la microarchitecture de ce système fonctionnel, variant d'un organe à l'autre, une thérapie ne peut pas «convenir pour tout». Les altérations observées dans la microcirculation sevèrement endommagée sont de 3 ordres: (i) le contenant défini par les différentes couches de la paroi vasculaire, y compris les cellules endothéliales et un gel protecteur appelé glycocalyx répandu à la surface, où le contact avec le sang est établi, (ii) le contenu représentant le plasma qui coule avec les différents éléments figures du sang et (iii) les tissus extraluminaux environnants. La microcirculation peut être endommagée de diverses manières, avec différents niveaux de dommage à ces éléments constitutifs. Ainsi, pour réanimer de manière appropriée la microcirculation lésée, le choix de la thérapie optimale ou du faisceau de thérapies doit être rationalisé avec une analyse méticuleuse des dommages subis par la microcirculation. Ainsi, l'évaluation de la microcirculation doit être obligatoirement multivariée. Dans cette thèse, la recherche s'est principalement concentrée sur un organe, le rein. La première partie est consacrée à la revue des mécanismes structurels et fonctionnels de la microcirculation rénale en condition physiologique et également septique. La deuxième partie tente d'identifier les rôles respectifs de chacun des composants de la microcirculation dans des conditions critiques notamment le glycocalyx et la viscosité du plasma. La perméabilité de la barrière vasculaire a été étudiée dans les modèles de choc hémorragique et d'hémodilution chez les rongeurs. Les principaux résultats suggèrent qu'il existe une gradation du niveau de lésion de la barrière vasculaire. La dernière partie de la thèse a examiné comment les thérapies actuelles et anciennes peuvent moduler la microcirculation en termes d'oxygénation, d'inflammation et de flux microcirculatoire dans le rein. Parmi les thérapies étudiées, la N-acétylcystéine était efficace pour limiter l'inflammation et augmenter l'oxygénation dans le rein. Une nouvelle génération de transporteur d'oxygène à base d'hémoglobine a montré une certaine efficacité dans le modèle endotoxémique murin. Dans l'ensemble, ces différents résultats se rejoignent pour montrer l'importance d'avoir une analyse multivariée de la microcirculation, car chacune des thérapies agit sur un aspect spécifique de celle-ci. Nous espérons que les résultats de cette recherche ouvrent la voie à une médecine plus personnalisée pour les patients.

Objective: Handheld vital microscopy (HVM) enables bedside visualization of the microcirculation, with major improvements from sidestream darkfield (SDF) to incident dark field (IDF) imaging. Although IDF offers high‐resolution images, standard analysis methods require down‐sampling to match SDF's lower field of view (FOV) and pixel density. MicroTools, an automated stabilization and analysis algorithm, has previously been validated for use with SDF image sequences. This study aimed to assess the accuracy and precision of microcirculatory analysis using MicroTools on full‐frame, high‐resolution IDF images. Methods: Image sequences from a previous study were re‐analyzed in both IDF and down‐sampled SDF formats. Microcirculatory parameters—including total vessel density (TVD), functional capillary density, and red blood cell velocity (RBCv)—were compared between formats. MicroTools' new stabilization algorithm was also evaluated against existing algorithms. Results: Full‐frame IDF analysis increased the FOV by 200% and pixel density by 66%, enhancing capillary detection and TVD measurements. RBCv values were lower with IDF images. The updated stabilization algorithm showed performance comparable to prior methods. Conclusions: MicroTools analysis of full‐frame IDF images improved measurement accuracy and vessel detection, with excellent agreement to standard software. Its new stabilization algorithm proved equally robust, supporting broader adoption in clinical research.

The endothelial glycocalyx (GCX) is a specialized form of extracellular matrix with a dynamic synthesis and degradation balance. It plays a pivotal role in regulating cell signaling, sensing the extracellular environment, and maintaining vascular permeability. In the setting of heart failure (HF), particularly in HF with preserved ejection fraction (HFpEF), systemic endothelial GCX degradation may represent an early pathophysiological mechanism. Indeed, HFpEF results from comorbidities-related proinflammatory states leading to endothelial dysfunction and subsequent myocardial hypertrophy, fibrosis, and stiffening. Endothelial GCX degradation is mainly triggered by matrix metalloproteinases, specific degradation enzymes (heparanase, hyaluronidase), or reactive oxygen species (ROS). Preservation or restoration of endothelial GCX function via GCX components’ injection, enzyme inhibitors, anticoagulants, or dietary supplements has increasingly emerged as a promising approach to limit HFpEF progression. This review provides an overview of GCX degradation markers in HFpEF and summarizes current knowledge on the possible GCX’s role in HFpEF pathophysiology.

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.

Infections of the aorta and its branches can occur either in native tissue, known as infective native aortic aneurysms (INAAs), or following vascular surgery involving native or prosthetic grafts, referred to as vascular graft or endograft infections (VGEIs). First, this study aimed to assess the all-cause on-year mortality of patients with INAAs and VGEIs. Second, this study described patients' characteristics and prognostic factors. This observational study included patients hospitalised for INAA or VGEI, between 2014 and 2022, at Nancy University Hospital (France). Data were retrospectively collected from patients' medical record (ClinicalTrials.gov ID NCT05660733). Forty-seven patients were included in the INAAs group versus 40 in the VGEIs group. A history of immunosuppression or autoimmune disease were more frequent in INAAs patients. VGEIs patients had more chronic organ failure or cardiovascular pathology. The most commonly affected site was the infrarenal aorta, with thoracic involvement being more frequent in the INAAs group. Staphylococcus aureus was the most frequent identified pathogen (38.3% vs. 27.5%). There was no significant difference between groups in terms of all-cause 1-year mortality (40.4% in the INAAs group vs. 32.5% in the VGEIs group, log-rank test, p = .4803). The absence of surgery worsened the prognosis in the overall population (HR 2.8, 95% CI [1.2-6.3], p = .0125); this was also observed in the INAA group. Despite different comorbidities and clinical presentations between groups, there was no significant difference in 1-year mortality. Surgical management appeared to be associated with improved outcomes.

Introduction: Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population. Methods and analysis: CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR 2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in μmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m ² ), at 1 year, 3 years and 10 years after transplantation. Ethics and dissemination: This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels. Trial registration number: NCT04714710 .

Background: The understanding of high mortality associated with intra-abdominal candidiasis (IAC) remains limited. While Candida is considered a harmless colonizer in the digestive tract, its role as a true pathogen in IAC is still debated. Evidence regarding Candida virulence in the human peritoneal fluid are lacking. We hypothesized that during IAC, Candida albicans develops virulence factors to survive to new environmental conditions. The objective of this observational exploratory monocentric study is to investigate the influence of peritoneal fluid (PF) on the expression of C. albicans virulence using a multimodal approach. Materials and methods: A standardized inoculum of a C. albicans (3.10⁶ UFC/mL) reference strain (SC5314) was introduced in vitro into various PF samples obtained from critically ill patients with intra-abdominal infection. Ascitic fluids (AFs) and Sabouraud medium (SBD) were used as control groups. Optical microscopy and conventional culture techniques were employed to assess the morphological changes and growth of C. albicans. Reverse transcriptase qPCR was utilized to quantify the expression levels of five virulence genes. The metabolic production of C. albicans was measured using the calScreener™ technology. Results: A total of 26 PF samples from patients with secondary peritonitis were included in the study. Critically ill patients were mostly male (73%) with a median age of 58 years admitted for urgent surgery (78%). Peritonitis was mostly hospital-acquired (81%), including 13 post-operative peritonitis (50%). The infected PF samples predominantly exhibited polymicrobial composition. The findings revealed substantial variability in C. albicans growth and morphological changes in the PF compared to ascitic fluid. Virulence gene expression and metabolic production were dependent on the specific PF sample and the presence of bacterial coinfection. Conclusions: This study provides evidence of C. albicans virulence expression in the peritoneal fluid. The observed variability in virulence expression suggests that it is influenced by the composition of PF and the presence of bacterial coinfection. These findings contribute to a better understanding of the complex dynamics of intra-abdominal candidiasis and advocate for personalized approach for IAC patients. Trial registrationhttps://clinicaltrials.gov/ (NCT05264571; February 22, 2022) Graphical