Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury

International audienceIssues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations.To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients.The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p\textless0.001) and VAP onset ≥10 days (p\textless0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770-0.883) in the learning cohort and 0.805 (95% CI 0.732-0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596-0.751).Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts \textless48 

Overview of the current use of levosimendan in France: a prospective observational cohort study

Abstract Background Following the results of randomized controlled trials on levosimendan, French health authorities requested an update of the current use and side-effects of this medication on a national scale. Method The France-LEVO registry was a prospective observational cohort study reflecting the indications, dosing regimens, and side-effects of levosimendan, as well as patient outcomes over a year. Results The patients included ( n = 602) represented 29.6% of the national yearly use of levosimendan in France. They were treated for cardiogenic shock ( n = 250, 41.5%), decompensated heart failure ( n = 127, 21.1%), cardiac surgery-related low cardiac output prophylaxis and/or treatment ( n = 86, 14.3%), and weaning from veno-arterial extracorporeal membrane oxygenation ( n = 82, 13.6%). They received 0.18 ± 0.07 µg/kg/min levosimendan over 26 ± 8 h. An initial bolus was administered in 45 patients (7.5%), 103 (17.1%) received repeated infusions, and 461 (76.6%) received inotropes and or vasoactive agents concomitantly. Hypotension was reported in 218 patients (36.2%), atrial fibrillation in 85 (14.1%), and serious adverse events in 17 (2.8%). 136 patients (22.6%) died in hospital, and 26 (4.3%) during the 90-day follow-up. Conclusions We observed that levosimendan was used in accordance with recent recommendations by French physicians. Hypotension and atrial fibrillation remained the most frequent side-effects, while serious adverse event potentially attributable to levosimendan were infrequent. The results suggest that this medication was safe and potentially associated with some benefit in the population studied

MISE EN EVIDENCE DU RECEPTEUR BETA 3-ADRENERGIQUE DANS DIFFERENTS LITS VASCULAIRES HUMAINS

NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Les récepteurs b3-adrénergiques dans le système cardiovasculaire (rôles physiopathologiques et implications thérapeutiques)

Mon travail de thèse s est articulé autour de plusieurs projets complémentaires concernant le récepteur b3-adrénergique (b3-AR) dans le système cardiovasculaire. Nous avons identifié la présence de récepteurs b3-ARs sur l endothélium de l artère mammaire interne humaine, artère utilisée pour la revascularisation myocardique. Leur stimulation induit une vasodilatation dépendante de la voie du monoxyde d azote (NO). Ces récepteurs pourraient avoir un intérêt dans la prévention du vasospasme après pontage aortocoronarien. Actuellement, les cibles cellulaires des effets d un b-bloquant de 3ème génération efficace dans l hypertension artérielle et l insuffisance cardiaque, le nébivolol, étant mal connues, nous avons démontré qu il active les récepteurs b3-ARs à la fois dans l aorte thoracique de rat et dans le myocarde humain. La surexpression du récepteur b3-AR grâce à un vecteur adénoviral conduit à des effets pro-angiogéniques dans différents modèles expérimentaux. Dans le choc endotoxémique, la vasodilatation b3-AR est diminuée et peut être partiellement compensée par une potentialisation de la réponse induite par les récepteurs b1- et b2-ARs. L ensemble de ces résultats suggère un rôle potentiel des récepteurs b3-ARs dans différentes pathologies cardiovasculaires.My work of thesis was articulated around several complementary projects concerning the b3-adrenoceptor (b3-AR) in the cardiovascular system. We identified the presence of b3-ARs on internal mammary artery endothelium, an artery used as graft for the myocardial revascularisation. Their stimulation induces a vasodilation dependent of nitric oxyde (NO). These receptors could prevent vasospasm after coronary artery bypass surgery. Currently, the cellular targets of a third generation b-blocker efficient in systemic hypertension and heart failure, nebivolol, being poorly characterised, we shown that it activates b3-ARs both in rat thoracic aorta and in human myocardium. The overexpression of b3-AR by using an adenoviral vector, leads to pro-angiogenic effects in various angiogenesis assays. In endotoxemic shock, the b3-AR induced vasodilation is decreased, and is partly compensed by b1- and b2-AR activity potentialisation. Taken together theses results highlight the potential role of b3-AR in various cardiovascular diseases.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Altération du système bêta-adrénertique cardiaque au cours de la cardiotoxicité induite par la doxorubicine

NANTES-BU Sciences (441092104) / SudocSudocFranceF

Human heart failure with preserved ejection versus feline cardiomyopathy: what can we learn from both veterinary and human medicine?

International audienceCardiovascular affections are a growing health burden in human populations. Recent advances in cardiology have improved treatments and outcomes for myocardial infarction and arrhythmias, but other conditions still remain poorly understood. To date, the classical approach to study cardiovascular diseases involves rodent models, despite their strong differences with human cardiac physiology. In this context, this review will focus on the common traits between human and feline cardiac diseases, namely heart failure with preserved ejection fraction and feline cardiomyopathies, respectively. These two affections share similar pathological patterns and epidemiological characteristics. An improved knowledge would be of interest for both human and feline patients and could lead to the establishment of a more accurate treatment and therapeutic strategy for medical doctors and veterinary practitioners

Beta-3 adrenoceptors as new therapeutic targets for cardiovascular pathologies.

Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels. In cardiac ventricle, their contractile effects are functionally antipathetic to those of ß(1/2)-AR; in normal heart, ß(3)-ARs may mediate a moderate negative inotropic effect, but in heart failure, it may protect against adverse effects of excessive catecholamine stimulation by action on excitation-contraction coupling, electrophysiology, or remodelling. Thus, prospective studies in animals and patients at different stages of heart failure should lead to identify the best therapeutic window to use ß(3)-AR agonists and/or antagonists

Cost Analysis of Aprotinin Reintroduction in French Cardiac Surgery Centres: A Real-World Data-Based Analysis

International audienceIntroduction: The European Medicines Agency restored aprotinin (APR) use for preventing blood loss in patients undergoing isolated coronary artery bypass graft (iCABG) in 2016 but requested the collection of patient and surgery data in a registry (NAPaR). The aim of this analysis was to evaluate the impact of APR reintroduction in France on the main hospital costs (operating room, transfusion and intensive unit stay) compared to the current use of tranexamic acid (TXA), which was the only antifibrinolytic available before APR reinstatement.Methods: A multicenter before-after post-hoc analysis to compare APR and TXA was carried out in four French university hospitals. APR use followed the ARCOTHOVA (French Association of Cardiothoracic and Vascular Anesthetists) protocol, which had framed three main indications in 2018. Data from 236 APR patients were retrieved from the NAPaR (N = 874); 223 TXA patients were retrospectively retrieved from each center database and matched to APR patients upon indication classes. Budget impact was evaluated using both direct costs associated with antifibrinolytics and transfusion products (within the first 48 h) and other costs such as surgery duration and ICU stay.Results: The 459 collected patients were distributed as: 17% on-label; 83% off-label. Mean cost per patient until ICU discharge tended to be lower in the APR group versus the TXA group, which resulted in an estimated gross saving of €3136 per patient. These savings concerned operating room and transfusion costs but were mainly driven by reduced ICU stays. When extrapolated to the whole French NAPaR population, the total savings of the therapeutic switch was estimated at around €3 million.Conclusion: The budget impact projected that using APR according to ARCOTHOVA protocol resulted in decreased requirement for transfusion and complications related to surgery. Both were associated with substantial cost savings from the hospital’s perspective compared with exclusive use of TXA

New Approaches to Identify Sepsis Biomarkers: The Importance of Model and Sample Source for Mass Spectrometry

Septic shock is a systemic inflammatory response syndrome associated with circulatory failure leading to organ failure with a 40% mortality rate. Early diagnosis and prognosis of septic shock are necessary for specific and timely treatment. However, no predictive biomarker is available. In recent years, improvements in proteomics-based mass spectrometry have improved the detection of such biomarkers. This approach can be performed on different samples such as tissue or biological fluids. Working directly from human samples is complicated owing to interindividual variability. Indeed, patients are admitted at different stages of disease development and with signs of varying severity from one patient to another. All of these elements interfere with the identification of early, sensitive, and specific septic shock biomarkers. For these reasons, animal models of sepsis, although imperfect, are used to control the kinetics of the development of the pathology and to standardise experimentation, facilitating the identification of potential biomarkers. These elements underline the importance of the choice of animal model used and the sample to be studied during preclinical studies. The aim of this review is to discuss the relevance of different approaches to enable the identification of biomarkers that could indirectly be relevant to the clinical setting