Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsAP conceived the study, enrolled patients, performed the analysis and wrote the manuscript. AL ran the experiments and measured mitochondrial membrane potential. FF measured respiratory chain enzyme activities and revised the manuscript. table 5 AA participated in the study design, data analysis and revised the manuscript. NG ran the experiments and helped to draft the manuscript. SV participated in data analysis and helped to draft the manuscript. GF performed electron microscopy and revised the manuscript. MM participated in study design, data analysis and revised the manuscript. GPC participated in study design, data analysis and revised the manuscript. GM participated in data analysis and helped to draft the manuscript.

BL ran the experiments and revised the manuscript. LF ran the experiments and revised the manuscript. LG participated in study design, data analysis and revised the manuscript. All authors read and approved the final version of the manuscript.Supplementary MaterialAdditional File 1:Time-dependent effects of a highly toxic dose of metformin on human platelet mitochondrial function. Platelets from healthy donors were incubated in plasma with metformin diluted in saline (16,600 mg/L). (a) Plasma lactate concentration (P = 0.002; one-way repeated measures ANOVA) and (b) the ratio between normally polarized and abnormally depolarized platelet mitochondria (JC-1 fluorescence ratio) (P = 0.035; one-way repeated measures ANOVA) were measured every 24 hours, up to 72 hours.

Data are mean and SD, from three experiments. *P < 0.05 versus time 0 (Holm-Sidak method). ANOVA, analysis of variance; SD, standard deviation.Click here for file(18K, PDF)Additional File 2:Relationship between platelet mitochondrial function and lactate production. Platelets from healthy donors were incubated for 72 hours in plasma with metformin diluted in saline (concentrations ranging from 0 to 16,600 mg/L). Correlation (linear regression analysis) between final plasma lactate levels and (a) platelet complex I (CI) activity expressed relative to citrate synthase (CS) activity (R2 0.54, P = 0.001; n = 16), (b) platelet JC-1 fluorescence ratio (R2 0.37, P = 0.001; n = 32), and (c) platelet oxygen use (R2 0.82, P < 0.001; n = 27) are shown.

Click here for file(17K, PDF)Additional File 3:Dose-dependent effects of metformin on human platelet respiratory chain complex activities. Platelets from healthy donors were incubated in plasma with saline (white bar) Dacomitinib or metformin diluted in saline (concentration: 1.66 mg/L, grey bar; 166 mg/L, dark grey bar; or 16,600 mg/L, black bar). After 72 hours, the activity of (a) complex I (CI) (P = 0.009; one-way ANOVA), (b) complex II and III (CII+III) (P = 0.767; one-way ANOVA) and (c) complex IV (CIV) (P = 0.

Da Concei?ao et al. performed BAL in hypoxemic and hypercapnic sellekchem chronic obstructive pulmonary disease patients using bilevel ventilatory support [19].The use of bronchoscopy allows us to select the sampling site with chest X-ray. The low volume used for mini-BAL (20 ml) probably has a better tolerance than the larger volume used for BAL (250 ml).Based on our results, we agree with Brito et al. when they suggest that HCAP is a heterogeneous disease and that all patients do not need the same broad-spectrum antibiotic therapy [20]. Our bacteriological results are in agreement with this idea. Moreover, a recent study suggested that the HCAP concept does not correlate well with the presence of infection due to a resistant pathogen [5].

From our point of view, this debate promotes the use of an efficient pathogen identification technique to avoid the use of broad-spectrum antibiotics and to de-escalate initial antibiotics as soon as possible [21]. Besides, some authors propose to redefine the concept of HCAP which may contribute to confusion more than provide a guide to pneumonia management, and potentially leads to overtreatment [22]. Achieving bacteriological identification in a larger population study should define new HCAP criteria and adapt empirical antibiotic therapy to these new categories.Our study has several limitations. It appears that the main limitation of our strategy is the availability of the fiberoptic bronchoscope and an experienced operator when the patient is admitted to the emergency department.

Indeed, the examination should be completed promptly after hospital admittance so that antibiotic therapy can be started as soon as possible. We describe our local bacteriological ecology. It has been shown that pathogens and their drug-sensitivity may be different in other areas [3]. An additional limitation is that our study is observational. We did not compare the effectiveness of our strategy regarding outcomes with an antibiotic strategy based on non-invasive pathogen identification. Large scale, multi-center studies are needed to confirm our strategy regarding outcome, as well as ecological and economic costs.ConclusionsOur study demonstrates that early FODP mini-BAL is safe and more efficient than blood cultures to identify pathogens and de-escalate antibiotic therapy in patients presenting with HCAP.

We demonstrated that HCAP classification is relevant in our hospital. However, other studies are needed to compare the efficiency of this strategy Anacetrapib including mini-BAL with a non-invasive strategy including sputum cultures, blood cultures, and an epidemiologic approach in terms of outcome and the economic impact of early antibiotic de-escalation.Key messages? Early FODP mini-BAL is safe and more efficient than blood cultures to identify pathogens and de-escalate antibiotic therapy in the treatment of HCAP (46.

ConclusionsIn summary, our results show that a large-scale cohort of septic shock patients is feasible reference using simplified computer-based data collection, and shows that mortality among this patient group is still very high. This can be explained by the fact that patients with septic shock admitted to the ICU are generally older, with more co-morbidities, a worse previous state of health, and requiring more life-support therapies. These observations may be useful for quality improvement of the care provided to patients at risk of, or with confirmed septic shock, for the design of future clinical studies and for healthcare decision-makers.Key messages? This is the first large-scale epidemiological study performed in France since the publication of the Surviving Sepsis Campaign recommendations and of French national guidelines for the management of septic shock.

? Mortality in the ICU among patients admitted for septic shock is declining, or rather, death occurs at a later stage. In-hospital mortality has remained constant for many years, likely due to better initial management.? The older age, greater dependency, and more frequent co-morbidities among ICU patients admitted for septic shock probably also explain why overall mortality has remained stable over time.? Mortality at 28 days after an initial episode of septic shock in the ICU was 42% in this prospective, multicenter, cohort study from 14 ICUs in 10 public hospitals in France. Main factors significantly associated with time to death, right censored at 28 days were age, Knaus, and SOFA scores.

AbbreviationsICU: Intensive Care Unit; IQR: interquartile range; SAPS II: Simplified Acute Physiological Score II; SD: standard deviation; SOFA: Sepsis-related Organ Failure Assessment.Competing interestsThe authors declare that Carfilzomib they have no competing interests.Authors’ contributionsStudy conception and design: JPQ, CB, AP; Data acquisition: All authors; Study coordination: VC, JC, GL, PP, AN; Statistical analysis: JPQ, CB, AP; Drafting of the manuscript: JPQ, CB, AP, FG, JCN; Critical revision of the manuscript: All; Final approval of the manuscript for submission: All.AcknowledgementsThe authors thank Fiona Ecarnot for translation and editorial assistance and Amel Mahboubi for help with the statistical analysis.