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Purpose Our objective was to estimate the impact of the absence of Out-of-Bed (OoB) mobilization during intensive care unit (ICU) stay among patients ≥70 years on their long-term autonomy. Methods We conducted an ancillary study of the multicenter FRAGIREA study, including patients aged over 70 years, admitted to ICU for more than 48 h. We excluded the patients who died before day 180, who were lost to follow-up, and for whom the baseline autonomy (ADL) score was not available. Patients were classified into the OoB or non-OoB-mobilization group, and the impact of OoB mobilization on the decreased 6-month autonomy was estimated. Results Among the 548 patients of the FRAGIREA cohort, 276 were included in the present study. Among them, 226 had OoB mobilization and 50 did not. 220/276 (80%) patients experienced the transfer to chair as rehabilitation therapy, passive mobilization and transfer to upright sitting were also frequently performed. A decrease in the 6-month autonomy was observed for 63 (23%) patients. After the elimination of potential confounders, non-OoB-mobilization patients had a greater risk of 6-month decreased autonomy (aOR 2.43 [1.18; 4.98]). Conclusions Mobilization during the ICU stay of elderly ICU patient survivors was associated with a lower decreased autonomy at 6 months.

SARS-Cov-2 (COVID-19) has become a major worldwide health concern since its appearance in China at the end of 2019.To evaluate the intrinsic mortality and burden of COVID-19 and seasonal influenza pneumonia in ICUs in the city of Lyon, France.A retrospective study.Six ICUs in a single institution in Lyon, France.Consecutive patients admitted to an ICU with SARS-CoV-2 pneumonia from 27 February to 4 April 2020 (COVID-19 group) and seasonal influenza pneumonia from 1 November 2015 to 30 April 2019 (influenza group). A total of 350 patients were included in the COVID-19 group (18 refused to consent) and 325 in the influenza group (one refused to consent). Diagnosis was confirmed by RT-PCR. Follow-up was completed on 1 April 2021.Differences in 90-day adjusted-mortality between the COVID-19 and influenza groups were evaluated using a multivariable Cox proportional hazards model.COVID-19 patients were younger, mostly men and had a higher median BMI, and comorbidities, including immunosuppressive condition or respiratory history were less frequent. In univariate analysis, no significant differences were observed between the two groups regarding in-ICU mortality, 30, 60 and 90-day mortality. After Cox modelling adjusted on age, sex, BMI, cancer, sepsis-related organ failure assessment (SOFA) score, simplified acute physiology score SAPS II score, chronic obstructive pulmonary disease and myocardial infarction, the probability of death associated with COVID-19 was significantly higher in comparison to seasonal influenza [hazard ratio 1.57, 95% CI (1.14 to 2.17); P = 0.006]. The clinical course and morbidity profile of both groups was markedly different; COVID-19 patients had less severe illness at admission (SAPS II score, 37 [28 to 48] vs. 48 [39 to 61], P 0.001 and SOFA score, 4 [2 to 8] vs. 8 [5 to 11], P 0.001), but the disease was more severe considering ICU length of stay, duration of mechanical ventilation, PEEP level and prone positioning requirement.After ICU admission, COVID-19 was associated with an increased risk of death compared with seasonal influenza. Patient characteristics, clinical course and morbidity profile of these diseases is markedly different.

It has been suggested to define the Trauma-induced coagulopathy (TIC) with a PTRetrospective analysis of prospectively collected data of 1076 severely injured patients admitted from 01/2011 to 12/2019 in a university hospital. To determine the number of TIC categories and the best PTThree thresholds were, respectively, identified for PTIn this study, we have described a pragmatic classification of coagulopathy utilizing PT

Purpose Antibiotics are frequently used in patients receiving intermittent or continuous renal replacement therapy (RRT). RRT may alter the pharmacokinetics (PK), as well as the ability to achieve PK/pharmacodynamic (PD) targets. Therapeutic drug monitoring (TDM) could help evaluatedrug exposure and guide antibiotic dosage adjustment. The present review describes recent TDM data on antibiotic exposure and PK/PD target attainment in patients receiving intermittent or continuous RRT, proposing practical guidelines for performing TDM. Methods Studies on antibiotic TDM performed in patients receiving intermittent or continuous RRT published between 2000 and 2020 were searched and assessed. The authors focused on studies that reported data on PK/PD target attainment. TDM recommendations were based on clinically relevant PK/PD relationships and previously published guidelines. Results In total, 2383 reports were retrieved. After excluding non-relevant publications, 139 articles were selected. Overall, 107 studies reported PK/PD target attainment for 24 agents. Data were available for various intermittent and continuous RRT techniques. The study design, TDM practice, and definition of PK/PD targets were inconsistent across studies. Drug exposure and target attainment rates were highly variable. TDM appears necessary to control drug exposure in patients receiving intermittent and continuous RRT techniques, especially for antibiotics with narrow therapeutic margins and in critically ill patients. Practical recommendations can provide insights on relevant PK/PD targets, sampling, and timing of TDM for various antibiotic classes. Conclusion Highly variable antibiotic exposure and target attainment have been reported in patients receiving intermittent or continuous RRT. TDM for aminoglycosides, beta-lactams, glycopeptides, linezolid, and colistin is recommended in patients receiving RRT and suggested for daptomycin, fluoroquinolones, and tigecycline in critically ill patients on RRT.

We describe a March 2020 co-occurrence of Legionnaires' disease (LD) and coronavirus disease in France. Severe acute respiratory syndrome coronavirus 2 co-infections were identified in 7 of 49 patients from LD case notifications. Most were elderly men with underlying conditions who had contracted severe pneumonia, illustrating the relevance of co-infection screening.

Serious adverse events, such as wrong-side, wrong-organ, wrong-procedure, or wrong-person errors, still occur despite the implementation of preventative measures. In France, we describe the claims related to such errors based on the database from one of the main insurance companies.A retrospective analysis of claims declared between January 2007 and December 2017 to Relyens, a medical liability insurance company (Sham), was performed. Their database was queried using the following keywords: "wrong side," "wrong organ," and "wrong person."We collected 219 claims (0.4% of the total claims). The main specialties involved were orthopedics (34% of cases), neurosurgery (14%), and dentistry (14%). The claims were related to wrong organ (44%), side (39%), identity (13%), or procedure (4%). Juridical entity involved were mainly public facility (69%), followed by private facility (19%) or private physician (10%). The mean number of annual claims made has decreased of 20% since the mandatory implementation of the checklist in 2010 (22 versus 17.5 events per year). The main risk factors identified according to the ALARM protocol were factor related to the team (87%) or to the task to accomplish (78%). A direct causal factor was involved in 20% of the files, the main one being the organization (43%) closely related to the medical file (36%). The settlement was performed by conciliation in 69% of the claim and in court in 30%. The compensation was higher during a court settlement.Wrong-side, wrong-organ, wrong-procedure, or wrong-person surgical errors are rare but fully preventable by the implementation of a safety culture.

CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.

Summary A survey was undertaken to evaluate the level of computerization in intensive care units (ICUs) within a French network dedicated to the surveillance of healthcare-associated infections, antimicrobial use (AMU) and antimicrobial resistance (AMR) in ICUs (REA-REZO). Ninety-eight ICUs responded, and patient records were computerized in 57%, antimicrobial prescriptions were computerized in 59% and AMR epidemiology was computerized in 72%. AMU and AMR feedback was provided to the ICU itself for 77% and 65% of ICUs, respectively, and feedback was provided to the national surveillance for 79% and 65% of ICUs, respectively. This study suggests that the level of computerization in ICUs requires further improvement.

BACKGROUND For more than 20 years, hip fracture 1-year mortality has remained around 20%. An elevation of the postoperative troponin peak within 72 hours (myocardial injury after noncardiac surgery [MINS]) is associated with a greater risk of short-term mortality in the general population. However, there seem to be conflicting results in the specific population who undergo hip fracture surgery, with some studies finding an association between troponin and mortality and some not. The objective of the present study was to investigate the association of MINS and the short- (before 28th day), intermediate- (before 180th day), and long-term (before 365th day) mortality after hip fracture surgery. METHODS We conducted a single-center retrospective cohort of patients undergoing hip fracture surgery from November 2013 to December 2015. MINS was defined as postoperative troponin peak within the 72 hours >5 ng/L. Four MINS subgroups were defined according to the value of troponin peak (ie, ≥5

To the Editor: Acute kidney injury (AKI) is a lesser-known complication of hip fracture that may come about owing to decreased kidney perfusion and heightened inflammation from trauma, pain, bleeding, and fasting. Approximately 15%-20% of patients undergoing surgery for a hip fracture develop AKI, with 0.5%-1.8% receiving dialysis. [...]

Background In severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is −1, but some teams have suggested to use higher thresholds (fibrinogenemia −1 or FIBTEM clot amplitude at 5 min (A5) values Methods Prospective analysis of retrospectively collected data from a trauma registry (01/2011–12/2019). MFD-C was defined by a fibrinogenemia 1.51–1.99 g L−1 or the corresponding FIBTEM-A5 values (MFD-A5) that were determined from linear regression and ROC curve analysis. Administration of fibrinogen were described according to the following admission parameters: shock index (SI) > 1, hemoglobin level −1 (HemoCue®), and base deficit > 5 mEq L−1. Data are expressed as count (%), median [IQR]. Results 1076 patients were included in the study and 266 (27%) had MFD-C, among them, 122/266 (46%) received fibrinogen. Patients with MFD-C who received fibrinogen were more severely injured (ISS: 27 [19–36] vs. 24 [17–29]) and had more impaired vital signs (base deficit: 5.4 [3.6–7.8] vs. 3.8 [2.0–6.0]). Linear regression analysis found a positive correlation between fibrinogen level and FIBTEM-A5 (r: 0.805). For a fibrinogen level −1 and −1, FIBTEM-A5 thresholds were 6 mm (sensitivity 85%, specificity 83%, AUC: 0.934) and 9 mm (sensitivity 84%, specificity 69%, AUC: 0.874), respectively. MFD-A5 values (185 (27%) patients) were defined as a FIBTEM-A5 between 7 and 9 mm. More than 50% of MFD-C patients presenting a SI > 1, a hemoglobin level −1, or a base deficit > 5.0 mEq L−1 received fibrinogen. The relative risk [95% CI] for fibrinogen administration (SI > 1) were 1.39 [1.06–1.82] for MFD-C, and 2.17 [1.48–3.19] for MFD-A5. Results were not modified after adjustment on the ISS. Conclusions We have shown in this study an association between shock parameters and fibrinogen administration. Further studies are needed to determine how these parameters may be used to guide fibrinogen administration in trauma patients with MFD.

Objective To compare old patients hospitalized in ICU for respiratory distress due to COVID-19 with old patients hospitalized in ICU for a non-COVID-19-related reason in terms of autonomy and quality of life. Design Comparison of two prospective multi-centric studies. Setting This study was based on two prospective multi-centric studies, the Senior-COVID-Rea cohort (COVID-19-diagnosed ICU-admitted patients aged over 60) and the FRAGIREA cohort (ICU-admitted patients aged over 70). Patients We included herein the patients from both cohorts who had been evaluated at day 180 after admission (ADL score and quality of life). Interventions None. Measurements and main results A total of 93 COVID-19 patients and 185 control-ICU patients were included. Both groups were not balanced on age, body mass index, mechanical ventilation, length of ICU stay, and ADL and SAPS II scores. We modeled with ordered logistic regression the influence of COVID-19 on the quality of life and the ADL score. After adjustment on these factors, we observed COVID-19 patients were less likely to have a loss of usual activities (aOR [95% CI] 0.47 [0.23; 0.94]), a loss of mobility (aOR [95% CI] 0.30 [0.14; 0.63]), and a loss of ADL score (aOR [95% CI] 0.30 [0.14; 0.63]). On day 180, 52 (56%) COVID-19 patients presented signs of dyspnea, 37 (40%) still used analgesics, 17 (18%) used anxiolytics, and 14 (13%) used antidepressant. Conclusions COVID-19-related ICU stay was not associated with a lower quality of life or lower autonomy compared to non-COVID-19-related ICU stay.

OBJECTIVES: Little is known about the epidemiology of ventilator-acquired pneumonia among coronavirus disease 2019 patients such as incidence or etiological agents. Some studies suggest a higher risk of ventilator-associated pneumonia in this specific population. DESIGN: Cohort exposed/nonexposed study among the REA-REZO surveillance network. SETTING: Multicentric; ICUs in France. PATIENTS: The coronavirus disease 2019 patients at admission were matched on the age, sex, center of inclusion, presence of antimicrobial therapy at admission, patient provenance, time from ICU admission to mechanical ventilation, and Simplified Acute Physiology Score II at admission to the patients included between 2016 and 2019 within the same surveillance network (1:1). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall incidence of ventilator-associated pneumonia, the cumulative incidence, and hazard rate of the first and the second ventilator-associated pneumonia were estimated. In addition, the ventilator-associated pneumonia microbiological ecology and specific resistant pattern in coronavirus disease 2019 exposed and nonexposed patients were compared. Medication data were not collected. A total of 1,879 patients were included in each group. The overall incidence of ventilator-associated pneumonia was higher among coronavirus disease 2019 exposed patients (25.5; 95% CI [23.7-27.45] vs 15.4; 95% CI [13.7-17.3] ventilator-associated pneumonia per 1,000 ventilation days). The cumulative incidence was higher for the first and the second ventilator-associated pneumonia among the coronavirus disease 2019 exposed patients (respective Gray test p < 0.0001 and 0.0167). The microbiological ecology and resistance were comparable between groups with a predominance of Enterobacterales and nonfermenting Gram-negative bacteria. The documented resistance pattern was similar between groups, except for a lower rate of methicillin-resistant Staphylococcus aureus in the coronavirus disease 2019 exposed patient (6% vs 23%; p = 0.013). CONCLUSIONS: There was a higher incidence of ventilator-associated pneumonia occurring among coronavirus disease 2019 patient compared with the general ICU population, with a similar microbiological ecology and resistance pattern.

BackgroundThe prevalence of venous thromboembolic event (VTE) and arterial thromboembolic event (ATE) thromboembolic events in patients with COVID-19 remains largely unknown.MethodsIn this meta-analysis, we systematically searched for observational studies describing the prevalence of VTE and ATE in COVID-19 up to 30 September 2020.ResultsWe analysed findings from 102 studies (64 503 patients). The frequency of COVID-19-related VTE was 14.7% (95% CI 12.1% to 17.6%, I2=94%; 56 studies; 16 507 patients). The overall prevalence rates of pulmonary embolism (PE) and leg deep vein thrombosis were 7.8% (95% CI 6.2% to 9.4%, I2=94%; 66 studies; 23 117 patients) and 11.2% (95% CI 8.4% to 14.3%, I2=95%; 48 studies; 13 824 patients), respectively. Few were isolated subsegmental PE. The VTE prevalence was significantly higher in intensive care unit (ICU) (23.2%, 95% CI 17.5% to 29.6%, I2=92%, vs 9.0%, 95% CI 6.9% to 11.4%, I2=95%; pinteractioninteraction=0.04). The frequency rates of overall ATE, acute coronary syndrome, stroke and other ATE were 3.9% (95% CI 2.0% to to 3.0%, I2=96%; 16 studies; 7939 patients), 1.6% (95% CI 1.0% to 2.2%, I2=93%; 27 studies; 40 597 patients) and 0.9% (95% CI 0.5% to 1.5%, I2=84%; 17 studies; 20 139 patients), respectively. Metaregression and subgroup analyses failed to explain heterogeneity of overall ATE. High heterogeneity limited the value of estimates.ConclusionsPatients admitted in the ICU for severe COVID-19 had a high risk of VTE. Conversely, further studies are needed to determine the specific effects of COVID-19 on the risk of ATE or VTE in less severe forms of the disease.

International audience; INTRODUCTION: With the spread of COVID-19 epidemic, health plans must be adapted continuously. There is an urgent need to define the best care courses of patients with COVID-19, especially in intensive care units (ICUs), according to their individualised benefit/risk ratio. Since older age is associated with poorer short-term and long-term outcomes, prediction models are needed, that may assist clinicians in their ICU admission decision. Senior-COVID-Rea was designed to evaluate, in patients over 60 years old admitted in ICU for severe COVID-19 disease, the impact of age and geriatric and paraclinical parameters on their mortality 30 days after ICU admission. METHODS AND ANALYSIS: This is a multicentre survey protocol to be conducted in seven hospitals of the Auvergne-Rhône-Alpes region, France. All patients over 60 years old admitted in ICU for severe COVID-19 infection (or their legally acceptable representative) will be proposed to enter the study and to fill in a questionnaire regarding their functional and nutritional parameters 1 month before COVID-19 infection. Paraclinical parameters at ICU admission will be collected: lymphocytes and neutrophils counts, high-fluorescent lymphoid cells and immature granulocytes percentages (Sysmex data), D-dimers, C-reactive protein, lactate dehydrogenase (LDH), creatinine, CT scan for lung extension rate as well as clinical resuscitation scores, and the delay between the first signs of infection and ICU admission. The primary outcome will be the overall survival at day 30 post-ICU admission. The analysis of factors predicting mortality at day 30 will be carried out using univariate and multivariate logistic regressions. Multivariate logistic regression will consider up to 15 factors.The ambition of this trial, which takes into account the different approaches of geriatric vulnerability, is to define the respective abilities of different operational criteria of frailty to predict patients' outcomes. ETHICS AND DISSEMINATION: The study protocol was ethically approved. The results of the primary and secondary objectives will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04422340.

Increased preoperative delay in patients with hip fractures may be responsible for increased morbidity and mortality. We hypothesized that a strategy of reversal of vitamin K antagonist (VKA) by prothrombin complexes concentrates (PCCs), as compared to vitamin K, is safe and reduces preoperative delay and hospital length of stay (LOS).In this pilot study, we reviewed the records of patients admitted to a university-affiliated hospital for hip fracture between Jan. 1, 2012, and Dec. 31, 2016, who were taking VKA. Patients were stratified according to reversal strategy (vitamin K v. PCC). Adverse effects, time to surgery, LOS and mortality were collected from the electronic medical record and were compared between the 2 study groups and a control group not treated with VKA.A total of 141 patients were included in the study: 65 in the vitamin K group, 26 in the PCC group and 50 in the control group. The median preoperative delay in the PCC group (20 h [interquartile range (IQR)] 13-25 h]) and the control group (20 h [IQR 15-33 h]) was lower than that in the vitamin K group (45 h [IQR 31-52 h]) (p0.001). Patients in the PCC group had a shorter median hospital LOS than those in the vitamin K group (6 d [IQR 4-9 d] v. 8 d [IQR 6-11 d], p0.05). No difference was observed in the proportion of patients who received a red blood cell transfusion, or had thrombotic or hemorrhagic complications. No difference in mortality at 12 months was observed between the groups.In patients with hip fracture, the use of PCCs as compared to vitamin K to reverse the effect of VKA significantly reduced preoperative delay and hospital LOS, and was not associated with an increase in the rates of thrombotic or hemorrhagic complications. Prospective studies involving a greater number of patients are required to confirm these promising results.L’allongement du délai préopératoire chez les patients atteints d’une fracture de la hanche pourrait expliquer l’augmentation de la morbidité et de la mortalité. Selon notre hypothèse, une stratégie d’inversion des antagonistes de la vitamine K (AVK) au moyen de concentrés de complexes prothrombiques (CCP), plutôt que de vitamine K, est sécuritaire et réduit le délai préopératoire et la durée du séjour hospitalier.Pendant cette étude pilote, nous avons passé en revue les dossiers de patients sous AVK admis dans un centre universitaire pour fracture de la hanche entre le 1er janvier 2012 et le 31 décembre 2016. Les patients ont été stratifiés selon la stratégie d’inversion choisie (vitamine K c. CCP). Les effets indésirables, le délai préopératoire, la durée du séjour hospitalier et la mortalité ont été recueillis à partir des dossiers médicaux électroniques et ont été comparés entre les 2 groupes de l’étude et un groupe témoin non sous AVK.En tout, 141 patients ont été inclus dans l’étude, 65 dans le groupe sous vitamine K, 26 dans le groupe sous CCP et 50 dans le groupe témoin. Le délai préopératoire médian pour le groupe sous CCP (20 h [éventail interquartile (ÉIQ)] 13–25 h]) et le groupe témoin (20 h [ÉIQ 15–33 h]) a été plus bref que pour le groupe sous vitamine K (45 h [ÉIQ 31–52 h]) (p0,001). Les patients du groupe sous CCP ont eu un séjour hospitalier médian plus bref que les patients du groupe sous vitamine K (6 j [ÉIQ 4–9 j] c. 8 j [ÉIQ 6–11 j]) (p0,05). Aucune différence n'a été observée quant à la proportion de patients ayant reçu une transfusion de culot globulaire ou ayant manifesté des complications thrombotiques ou hémorragiques. Aucune différence quant à la mortalité à 12 mois n'a été observée entre les groupes.Chez les patients atteints d’une fracture de la hanche, l’utilisation des CCP plutôt que de la vitamine K pour inverser l’effet des AVK a significativement abrégé le délai préopératoire et la durée du séjour hospitalier, et n’a pas été associée à une augmentation des taux de complications thrombotiques ou hémorragiques. Des études prospectives sur un plus grand nombre de patients sont nécessaires pour confirmer ces résultats prometteurs.

Amikacin is still a recommended option in emergency surgery. Current guidelines have suggested an amikacin dose of 15-20 mg/kg/24 h for intra-abdominal infections (IAI). Our objectives were to analyse amikacin pharmacokinetics (PK) and dosage requirements in patients who underwent emergency surgery, and to identify an optimal dosing approach. We performed a retrospective data analysis of patients who received amikacin for emergency surgery over 2.5 years, with measurement of both peak (C

Several studies have raised interest in the use of postoperative troponin levels to stratify risk of postoperative morbidity and mortality. In this study, postoperative troponin concentration after cytoreductive surgery (with or without hyperthermic intraoperative intraperitoneal chemotherapy) was associated with severe postoperative complications, and enhanced the predictive capability of a multivariable model focusing on postoperative complications.

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.

International audience; The aim of this study was to describe the proportion of multidrug-resistant microorganisms (MDROs) involved in ventilator-associated pneumonia (VAP) as the first hospital-acquired infection in 536 adults with restricted risk factors for MDRO-related infection. We found a significant decrease in the percentage of MDROs involved in VAP between 2003 and 2016 and this percentage increased when VAP occurred after day 10.

© 2020 Elsevier Ltd Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods: HIP ATTACK was an international, randomised, controlled trial done at 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were aged 45 years or older were eligible. Research personnel randomly assigned patients (1:1) through a central computerised randomisation system using randomly varying block sizes to either accelerated surgery (goal of surgery within 6 h of diagnosis) or standard care. The coprimary outcomes were mortality and a composite of major complications (ie, mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Patients, health-care providers, and study staff were aware of treatment assignment, but outcome adjudicators were masked to treatment allocation. Patients were analysed according to the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT02027896). Findings: Between March 14, 2014, and May 24, 2019, 27 701 patients were screened, of whom 7780 were eligible. 2970 of these were enrolled and randomly assigned to receive accelerated surgery (n=1487) or standard care (n=1483). The median time from hip fracture diagnosis to surgery was 6 h (IQR 4–9) in the accelerated-surgery group and 24 h (10–42) in the standard-care group (p

Background: Candidemia is a major cause of mortality in the intensive care unit (ICU). According to the Infectious Diseases Society of America (IDSA), an echinocandin is recommended as initial therapy and fluconazole as an alternative. In a context of echinocandin resistance development, the question arising is whether azoles are a suitable alternative to echinocandins for the treatment of candidemia in critically ill patients. Methods: A 3-year (2015–2017) retrospective multicentric cohort study was conducted. Adult patients with a diagnosis of candidemia during the ICU stay and treated with echinocandins or azoles were included. Demographic, clinical data, mycological data, and antifungal treatments were collected. Kaplan–Meier survival analysis, univariate analysis, and a multivariate logistic regression analysis using a propensity score with the inverse probability of treatment weighting method were performed. Findings: Seventy-nine patients (n = 79) were analyzed. Treatment success, as well as survival on day 90 (Kaplan–Meier survival analysis, log rank test, p = 0.542), were comparable between patients who received echinocandins (caspofungin (n = 47)) or azoles (fluconazole (n = 29) or voriconazole (n = 3)). A multivariable analysis demonstrated that higher SOFA score on the day of candidemia diagnosis and absence of adequate Candida source control were independently associated with a greater risk of 90-day mortality, whereas azoles treatment was not associated with an excess 90-day mortality. Interpretation: This study confirms that the use of azoles recommended for candidemia, mostly fluconazole, as a first-line therapy is a reasonable alternative to caspofungin for ICU patients in our institution. This needs to be included in local guidelines through antifungal stewardship programs. Keywords: Candidemia, Caspofungin, Fluconazole, Voriconazole, Mortality, Propensity score

Amikacin is commonly used for probabilistic antimicrobial therapy in critically ill patients with sepsis. Its narrow therapeutic margin makes it challenging to determine the right individual dose that ensures the highest efficacy target attainment rate (TAR) in this setting. This study aims to develop a new initial dosing approach for amikacin by optimizing the a priori TAR in this population. A population pharmacokinetic model was built with a learning data set from critically ill patients who received amikacin. It was then used to design an initial dosing approach maximizing a priori TAR for a target ratio of ≥8 for the peak concentration to the MIC (C(max)/MIC) or of ≥75 for the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC(0–24)/MIC). In the 166 patients included, 53% had amikacin C(max) of ≥64 mg/liter with a median dose of 23.4 mg/kg. A two-compartment model with creatinine clearance and body surface area as covariates best described the data and showed good predictive performance. Our dosing approach was successful in optimizing TAR for C(max)/MIC, with a rate of 92.9% versus 67.9% using a 30-mg/kg regimen, based on an external subset of data and assuming a MIC of 8 mg/liter. Mean optimal doses were higher (3.5 ± 0.5 g) than with the 30-mg/kg regimen (2.1 ± 0.3 g). Suggested doses varied with the MIC, the target index, and desired TAR threshold. A dosing algorithm based on the method is proposed for a large range of patient covariates. Clinical studies are necessary to confirm efficacy and safety of this optimized dosing approach.

Purpose Several remarks have been raised regarding the variables and cut-points used in the Sequential Organ Failure Assessment (SOFA) score. This study revisited the SOFA score and created a new simplified and accurate sa-SOFA score. Methods The study grouped four prospective cohorts (2005–2016) of patients with Systemic Inflammatory Response Syndrome. It collected 28-day mortality, sociodemographic characteristics, and the SOFA score with all variable values at Day 1. A logistic regression analysis was used to select the most relevant variables and a minimum p value approach with a 10-fold cross-validation were used to find the optimal partition of selected variables. The minimum number of cut-points (2, 3, or 4) was also tested by comparing the distributions of areas under receiver operating characteristic (AUROC) curves. Results Among the 1436 participants, 416 died within 28 days (28.9%). The sa-SOFA kept one variable per dimension and two cut-points per variable. The AUROC curves that investigated the abilities of the sa-SOFA and SOFA scores to predict 28-day mortality were 0.739 [0.712–0.768] and 0.687 [0.656–0.717], respectively (p-value of DeLong test Conclusion Keeping the conventional SOFA dimension variables, the new sa-SOFA proved to be simpler and more accurate in predicting 28-day mortality.

International audience; Amikacin antimicrobial effect has been correlated with the ratio of the peak concentration (Cmax ) to the minimum inhibitory concentration. A target Cmax >= 60-80 mg/L has been suggested. It has been shown that such target is not achieved in a large proportion of critically ill patients in intensive care units. A retrospective analysis was performed to examine the determinants of Cmax >= 80 mg/L on the first peak in 339 critically ill patients treated by amikacin. The influence of available variables on Cmax target attainment was analyzed using a classification and regression tree (CART) and logistic regression. Mean Cmax in the 339 patients was 73.0 \textpm 23.9 mg/L, with a target attainment rate (TAR, Cmax >= 80 mg/L) of 37.5%. In CART analysis, the strongest predictor of amikacin target peak attainment was dose per kilogram of lean body weight (dose/LBW). TAR was 60.1% in patients with dose/LBW >= 37.8 vs. 19.9% in patients with lower dose/LBW (OR = 6.0 (95% CI: 3.6-10.2)). Renal function was a secondary predictor of Cmax . Logistic regression analysis identified dose per kilogram of ideal body weight (OR = 1.13 (95% CI: 1.09-1.17)) and creatinine clearance (OR = 0.993 (95% CI: 0.988-0.998)) as predictors of target peak achievement. Based on our results, an amikacin dose >= 37.8 mg/kg of LBW should be used to optimize the attainment of Cmax >= 80 mg/L after the first dose in critically ill patients. An even higher dose may be necessary in patients with normal renal function.

OBJECTIVE Quick identification of septic source is fundamental in patients with severe sepsis of unknown origin. The purpose of this case report was to assess the benefit and feasibility of an early PET-CT in critically ill patients with undiagnosed sepsis. DATA SOURCES Clinical observations of two patients. STUDY SELECTION Case reports. DATA EXTRACTION Data extracted from medical records, after patient's consent. Illustrations were collected from the imaging software. DATA SYNTHESIS We admitted two critically ill patients for suspected sepsis and altered mental state. As all bacteriological samples were initially sterile, diagnostic workups in both patients led us to suspect underlying malignant hemopathy. In fact, the lumbar puncture of the first patient revealed a large B-cell lymphoma, and an acquired thrombotic thrombocytopenic purpura was suspected in the second patient. However, PET-CTs performed in both patients displayed infra-clinical underlying infectious foci. Within 48 hours, both patients developed a clearly identified sepsis linked to the described focus, and favorable outcome thanks to the precious information delivered by the PET-CT. CONCLUSIONS PET-CT precisely detected the deep foci of infection about 48 hours prior to the diagnosis of sepsis. The cases reports suggested the use of this image technique in ICU for patients with sepsis of unknown origin.

Severe septic syndromes deeply impair innate and adaptive immunity and are responsible for sepsis-induced immunosuppression. Although neutrophils represent the first line of defense against infection, little is known about their phenotype and functions a few days after sepsis, when the immunosuppressive phase is maximal (i.e., between d 3 and 8). The objective of the present study was to perform, for the first time, a global evaluation of neutrophil alterations in immunosuppressed septic patients (at d 3–4 and d 6–8) using phenotypic and functional studies. In addition, the potential association of these parameters and deleterious outcomes was assessed. Peripheral blood was collected from 43 septic shock patients and compared with that of 23 healthy controls. In the septic patients, our results highlight a markedly altered neutrophil chemotaxis (functional and chemokine receptor expressions), oxidative burst, and lactoferrin content and an increased number of circulating immature granulocytes (i.e., CD10dimCD16dim). These aspects were associated with an increased risk of death after septic shock. In contrast, phagocytosis and activation capacities were conserved. To conclude, circulating neutrophils present with phenotypic, functional, and morphologic alterations a few days after sepsis onset. These dysfunctions might participate in the deleterious role of sepsis-induced immunosuppression. The present results open new perspectives in the mechanisms favoring nosocomial infections after septic shock. They deserve to be further investigated in a larger clinical study and in animal models recapitulating these alterations.

Purpose Intensive care unit (ICU)-acquired infections (IAI) result in increased hospital and ICU stay, costs and mortality. To date, no biomarker has shown sufficient evidence and ease of application in clinical routine for the identification of patients at risk of IAI. We evaluated the association of the systemic mRNA expression of two host response biomarkers, CD74 and IL10, with IAI occurrence in a large cohort of ICU patients. Methods ICU patients were prospectively enrolled in a multicenter cohort study. Whole blood was collected on the day of admission (D1) and on day 3 (D3) and day 6 (D6) after admission. Patients were screened daily for IAI occurrence and data were censored after IAI diagnosis. mRNA expression levels of biomarkers were measured using RT-qPCR. Fine and Gray competing risk models were used to assess the association between gene expression and IAI occurrence. Results A total of 725 patients were analyzed. At least one IAI episode occurred in 137 patients (19%). After adjustment for shock and sepsis status at admission, CD74 and IL10 levels were found to be significantly associated with IAI occurrence [subdistribution hazard ratio (95% confidence interval) 0.67 (0.46–0.97) for CD74 D3/D1 expression ratio and 2.21 (1.63–3.00) for IL10 at D3]. IAI cumulative incidence was significantly different between groups stratified according to CD74 or IL10 expression (Gray tests p

A new pathway of three protein tyrosine kinase receptors, namely, the TAM receptor family [Tyro-3, Axl and Mer tyrosine kinase (MerTK)], has recently been described to negatively control immune responses. The objective of this prospective, observational, clinical study was to investigate the expression patterns of TAM receptors in circulating white blood cells collected from patients with septic shock.The expression of TAM receptors was measured by flow cytometry in circulating leukocytes from patients with septic shock sampled on days (D) 1-2 (n = 47) and D3-4 (n = 37) after the onset of shock, severe trauma patients at D1-2 after trauma (n = 51) and healthy individuals (n = 23).On D1-2 after injury, MerTK was overexpressed in monocytes and neutrophils collected from patients with septic shock in comparison with those collected from healthy volunteers and trauma patients. This phenomenon was also observed for mRNA. Conversely, the expression of Tyro-3 and Axl was higher in monocytes from trauma patients versus healthy volunteers or those in septic shock. MerTK expression between D1-2 and D3-4 remained elevated in patients suffering from septic shock who died or developed an intensive care unit-acquired infection, whereas it decreased in patients who recovered uneventfully. This in vivo observed expression pattern was reproduced ex vivo after the incubation of healthy volunteer cells with plasma from septic shock or trauma patients.MerTK expression in circulating innate immune cells is increased in patients with septic shock in comparison with healthy volunteers and trauma patients. Persistent MerTK overexpression after septic shock is associated with adverse outcome. The role of this family of receptors in the pathophysiology of injury-induced immune dysfunctions deserves to be specifically investigated.

Septic patients develop immune dysfunctions, the intensities and durations of which are associated with deleterious outcomes. LILRB2 (leukocyte immunoglobulin-like receptors subfamily B, member 2), an inhibitory member of the LILR family of receptors, is known for its immunoregulatory properties. In a microarray study, we identified LILRB2 as an upregulated gene in septic shock patients. On monocytes primed with LPS ex vivo, LILRB2 mRNA and protein expressions were dose-dependently downregulated and subsequently highly upregulated versus non-stimulated cells. This is concordant with clinical data, since both LILRB2 mRNA and protein expressions were significantly increased in septic shock patients at day 3. In a cohort of more than 700 patients, only after septic shock were LILRB2 mRNA levels increased compared with non-infected or less severely infected patients. This was preceded by a phase of downregulated mRNA expression during the first hours after septic shock. Interestingly, the intensity of this decrease was associated with increased risk of death after septic shock. LILRB2 protein and mRNA expressions are deregulated on monocytes after septic shock and this can be reproduced ex vivo after LPS challenge. Considering LILRB2 inhibitory properties, we can hypothesize that LILRB2 may participate in the altered immune response after septic shock.

Background Chemokine (C-X3-C motif) receptor 1 (CX3CR1) was identified as the most differentially expressed gene between survivors and non-survivors in two independent cohorts of septic shock patients and was proposed as a marker of sepsis-induced immunosuppression. Whether such a biomarker is associated with mortality in the heterogeneous group of critically ill patients is unknown. The primary objective of this study was to evaluate the association between CX3CR1 messenger RNA (mRNA) expression and mortality in intensive care unit (ICU) patients. The secondary objective was to evaluate similar endpoints in the subgroup of septic shock patients. Methods We performed a prospective, multicentre, non-interventional study in six ICUs of university hospitals in Lyon, France. Every consecutive adult patient with systemic inflammatory response syndrome and an expected length of stay in the ICU over 2 days was included. Whole-blood CX3CR1 mRNA expression was measured by quantitative real-time polymerase chain reaction at day 1 (D1) and D3 after inclusion. Results In ICU patients (n = 725), decreased CX3CR1 mRNA expression at D1 was associated with high D7 mortality (AUC 0.70, adjusted OR [aOR] 2.03, 95 % CI 1.19–3.46), while decreased expression at D3 was associated with increased D28 mortality (AUC 0.64, aOR 2.34, 95 % CI 1.45–3.77). In septic shock patients (n = 279), similar associations were observed between decreased D1 CX3CR1 mRNA expression and D7 mortality (AUC 0.69, aOR 2.76, 95 % CI 1.32–5.75) as well as decreased D3 expression and D28 mortality (AUC 0.72, aOR 3.98, 95 % CI 1.72–9.23). These associations were independent of lactacidaemia, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment score and Charlson comorbidity index. Conclusions This study represents the largest evaluation of such an mRNA marker in a heterogeneous cohort of severely injured patients. Our results show that decreased CX3CR1 mRNA expression is associated with increased mortality in ICU patients. This suggests a link between injury-induced immunosuppression and mortality in critically ill patients. In this context, the monitoring of such a host response molecular biomarker could prove very helpful for the identification of patients at high risk of death in the ICU. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1362-x) contains supplementary material, which is available to authorized users.

Sepsis represents the host's systemic inflammatory response to an infection. In this condition, immune response associates a marked inflammatory response and the delayed development of severe dysfunctions affecting both innate and adaptive responses. As neutrophils are the first line of defense against infection, they are central to the pathophysiology of sepsis in first hours. Nevertheless, their role during immunosuppression phase remains elusive. The main objective of the current work was to perform a transcriptomic study on purified neutrophils from septic shock patients (n=9) so as to identify genes that are differentially expressed during the first week after disease onset both (3-4 and 6-8days) versus healthy donors. Then, 45 septic shock patients were prospectively enrolled to confirm results at the protein level using flow cytometry. Twenty healthy volunteers (HV) were also included for the whole study. By comparing the transcriptome of purified neutrophils, we identified 364 up-regulated and 328 down-regulated genes differentially expressed. Of them, CD177 mRNA, coding for an activation molecule in chemotaxis, had the highest fold change modulation between patients and HV. This increase was then confirmed at the protein level. There was a constant subset of neutrophils that did not express CD177. However, when positive, septic neutrophils presented with significantly increased CD177 expression. Of note, no association between CD177 overexpression and features of immunosuppression has been highlighted. In addition, this up-regulation was negatively correlated with a decreased expression of CD10, a characteristic of immature myeloid cells. In conclusion, in this exploratory work, we shed light on the increased CD177 mRNA and protein expressions in circulating neutrophils after septic shock. Considering the potential dual roles of CD177 neutrophil (i.e., maturation/chemotaxis), negatively correlated in this study, its participation in septic shock pathophysiology deserves further investigation. Furthermore, its potential as a biomarker for sepsis would deserve to be investigated in large cohorts of patients.

International audience; OBJECTIVES:Low first-dose peak serum concentrations of amikacin and gentamicin are commonly reported in ICU patients. The present study aimed to assess whether 30 mg/kg amikacin or 8 mg/kg gentamicin achieved target concentrations in ICU patients with severe sepsis.PATIENTS AND METHODS:Sixty-three ICU patients (Simplified Acute Physiology Score II = 43 ± 16) with severe sepsis and an indication for intravenous amikacin (n = 47) or gentamicin (n = 16) were included. The first (30 mg/kg amikacin; 8 mg/kg gentamicin) and subsequent doses and corresponding peak concentrations (30 min after the completion of an infusion) were recorded. French guideline target concentrations were ≥60 and ≥30 mg/L for amikacin and gentamicin, respectively. A target pharmacokinetic/pharmacodynamic ratio of 10 × MIC was also measured.RESULTS:Pulmonary, abdominal and urinary tract infections were diagnosed in 56 patients. Infection was confirmed in 37 patients (59%). The targeted first-dose peak concentration was achieved in 37/63 patients (59%) [amikacin 36/47 (77%) and gentamicin 1/16 (6%)], and 59/63 patients (94%) achieved the pharmacokinetic/pharmacodynamic ratio using the MIC data that were available from 21 patients. However, the second dose of aminoglycoside was withheld because of high trough concentrations in nearly half of patients who did not have renal dysfunction.CONCLUSIONS:In this study, 30 mg/kg amikacin and 8 mg/kg gentamicin led to target peak serum concentrations in 59% of patients.

Background and objectives For patients suffering from peritoneal carcinomatosis, cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the only curative option. We focused on severe complications in the postoperative course of HIPEC. Methods We studied perioperative data from patients who underwent HIPEC between January 2010 and August 2011. Our primary objective was to identify perioperative risk factors for ICU admission. Our secondary objective was to identify patient that may be re-admitted to the ICU thanks to a prognostic score. Results 122 patients underwent HIPEC. 32 presented severe adverse events (26.2%) and 7 died (5.7%). Reasons for ICU admission were septic shock in 28.1% of patients, hemorrhagic shock for 21.9%, hemodynamic instability for 15.6%, respiratory causes for 6.2% and post-operative acidosis for 6.2%. Vasopressors were required for 34% and 40.6% were mechanically ventilated. Conclusion Peritoneal cancer index, diaphragmatic peritonectomy, the need of vasopressive therapy, total volume of fluid leakage collected in drains and total volume of fluid therapy administered at day 1 reported on ideal body weight were the 5 significant variables that we combined to build a morbidity prognostic score. One patient over 4 is likely to present severe complications. A predictive morbidity score provide informative data for clinicians.

Summary Background Intravascular-catheter-related infections are frequent life-threatening events in health care, but incidence can be decreased by improvements in the quality of care. Optimisation of skin antisepsis is essential to prevent short-term catheter-related infections. We hypothesised that chlorhexidine–alcohol would be more effective than povidone iodine–alcohol as a skin antiseptic to prevent intravascular-catheter-related infections. Methods In this open-label, randomised controlled trial with a two-by-two factorial design, we enrolled consecutive adults (age ≥18 years) admitted to one of 11 French intensive-care units and requiring at least one of central-venous, haemodialysis, or arterial catheters. Before catheter insertion, we randomly assigned (1:1:1:1) patients via a secure web-based random-number generator (permuted blocks of eight, stratified by centre) to have all intravascular catheters prepared with 2% chlorhexidine–70% isopropyl alcohol (chlorhexidine–alcohol) or 5% povidone iodine–69% ethanol (povidone iodine–alcohol), with or without scrubbing of the skin with detergent before antiseptic application. Physicians and nurses were not masked to group assignment but microbiologists and outcome assessors were. The primary outcome was the incidence of catheter-related infections with chlorhexidine–alcohol versus povidone iodine–alcohol in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01629550 and is closed to new participants. Findings Between Oct 26, 2012, and Feb 12, 2014, 2546 patients were eligible to participate in the study. We randomly assigned 1181 patients (2547 catheters) to chlorhexidine–alcohol (594 patients with scrubbing, 587 without) and 1168 (2612 catheters) to povidone iodine–alcohol (580 patients with scrubbing, 588 without). Chlorhexidine–alcohol was associated with lower incidence of catheter-related infections (0·28 vs 1·77 per 1000 catheter-days with povidone iodine–alcohol; hazard ratio 0·15, 95% CI 0·05–0·41; p=0·0002). Scrubbing was not associated with a significant difference in catheter colonisation (p=0·3877). No systemic adverse events were reported, but severe skin reactions occurred more frequently in those assigned to chlorhexidine–alcohol (27 [3%] patients vs seven [1%] with povidone iodine–alcohol; p=0·0017) and led to chlorhexidine discontinuation in two patients. Interpretation For skin antisepsis, chlorhexidine–alcohol provides greater protection against short-term catheter-related infections than does povidone iodine–alcohol and should be included in all bundles for prevention of intravascular catheter-related infections. Funding University Hospital of Poitiers, CareFusion.

High mobility group box 1 (HMGB1) is a highly conserved protein with multiple intracellular and extracellular functions, including transcriptional regulation, as well as modulation of inflammation, cell migration, and ingestion of apoptotic cells. In these experiments, we examined a potential role for intracellular HMGB1 in modulating phagocytosis. We found that phagocytosis of apoptotic cells resulted in translocation of HMGB1 into the cytoplasm and extracellular space. Transient or stable inhibition of HMGB1 expression in bone marrow-derived macrophages or fibroblasts resulted in increased phagocytosis of apoptotic thymocytes and apoptotic neutrophils. Knockdown of HMGB1 was associated with enhanced activation of Rac-1 and cytoskeletal rearrangement. Intracellular events involved in phagocytosis and upstream of Rac-1 activation, such as phosphorylation of ERK and focal adhesion kinase (FAK), were increased after knockdown of HMGB1. Inhibition of Src kinase activity prevented the increase in phosphorylation of FAK and ERK present during phagocytosis in HMGB1 knockdown cells, and also abrogated the enhancement in phagocytosis associated with HMGB1 knockdown. Interaction between Src and FAK in the cytoplasm of HMGB1 knockdown fibroblasts was enhanced compared with that present in control fibroblasts. Under in vitro conditions, the presence of HMGB1 diminished interactions between purified FAK and Src. These studies demonstrate a novel role for HMGB1 in the regulation of phagocytosis. In particular, these experiments show that intracellular HMGB1, through associating with Src kinase and inhibiting interactions between Src and FAK, diminishes the phagocytic ability of macrophages and other cell populations.

Enterococci may increase morbidity and mortality in elderly patients with intra-abdominal infections (IAIs) hospitalized in the intensive care unit (ICU).A single-centre, retrospective evaluation of an ICU database (1997-2007) of elderly ICU patients (≥75 years) with a severe IAI was performed. Demographics, severity scores, underlying diseases, microbiology and outcomes were recorded. Patients with enterococci isolated in peritoneal fluid (E+ group) were compared with those lacking enterococci in peritoneal fluid (E- group). Stepwise multivariate logistic regression was used to identify independent factors associated with mortality.One hundred and sixty patients were included (mean ± SD age 82 ± 5 years; n = 72 in the E+ group). The E+ group was more severely ill than the E- group, with higher Simplified Acute Physiologic Score 2 (61 ± 20 versus 48 ± 16, P = 0.0001) and Sequential Organ Failure Assessment scores (8 ± 3 versus 5 ± 3, P = 0.0001), a greater postoperative infection rate (58.3% versus 34.1%, P = 0.01), a higher incidence of inappropriate empirical antimicrobial therapies (33.3% versus 19.3%, P = 0.04), a longer duration of mechanical ventilation (11.8 ± 10.9 versus 7.8 ± 10.2 days, P = 0.02) and greater vasopressor use (7.2 ± 7.1 versus 3.3 ± 4.1 days, P = 0.001). ICU mortality was higher in the E+ group than in the E- group (54.2% versus 38.6%, P = 0.05). In the multivariate analysis, E+ status was independently associated with mortality (odds ratio 2.24; 95% confidence interval 1.06-4.75; P = 0.03).In severely ill, elderly patients in the ICU for an IAI, the isolation of enterococci was associated with increased disease severity and morbidity and was an independent risk factor for mortality.

Clearance of apoptotic cells by macrophages and other phagocytic cells, called efferocytosis, is a central process in the resolution of inflammation. Although the receptor for advanced glycation end products (RAGE) has been shown to participate in a variety of acute and chronic inflammatory processes in the lungs and other organs, a role for RAGE in efferocytosis has not been reported. In the present studies, we examined the potential involvement of RAGE in efferocytosis. Macrophages from transgenic RAGE−/− mice showed a decreased ability to engulf apoptotic neutrophils and thymocytes. Pretreatment of RAGE+/+ macrophages with advanced glycation end products, which competitively bind to RAGE, or Abs against RAGE diminished phagocytosis of apoptotic cells. Overexpression of RAGE in human embryonic kidney 293 cells resulted in an increased ability to engulf apoptotic cells. Furthermore, we found that incubation with soluble RAGE enhances phagocytosis of apoptotic cells by both RAGE+/+ and RAGE−/− macrophages. Direct binding of RAGE to phosphatidylserine (PS), an “eat me” signal highly expressed on apoptotic cells, was shown by using solid-phase ELISA. The ability of RAGE to bind to PS on apoptotic cells was confirmed in an adhesion assay. Decreased uptake of apoptotic neutrophils by macrophages was found under in vivo conditions in the lungs and peritoneal cavity of RAGE−/− mice. These results demonstrate a novel role for RAGE in which it is able to enhance efferocytosis through binding to PS on apoptotic cells.

Phagocytosis of apoptotic cells is critical to resolution of inflammation. High mobility group box 1 protein (HMGB1), a mediator of inflammation, has been shown to diminish phagocytosis through binding to phosphatidylserine (PS) exposed on the surface of apoptotic neutrophils. However, it is currently unknown whether HMGB1 also modulates the activity of receptors involved in PS recognition on the surface of phagocytes. In the present studies, we found that preincubation of macrophages with HMGB1 decreased their ability to engulf apoptotic neutrophils or thymocytes. Preincubation of macrophages with HMGB1 prevented the enhancement of efferocytosis resulting from exposure to milk fat globule EGF factor 8 (MFG-E8), an opsonin that bridges PS and αvβ3 as well as αvβ5-integrins on the surface of phagocytes. The inhibitory effect of HMGB1 on the phagocytic activity of macrophages was prevented by preincubation of HMGB1 with soluble αvβ3, but not with soluble αvβ5. HMGB1 colocalized with the β3-integrin on the cell membrane of macrophages and bound to soluble αvβ3, but not to soluble αvβ5. HMGB1 suppressed the interaction between MFG-E8 and αvβ3. HMGB1 also inhibited intracellular signaling events, including ERK phosphorylation and Rac-1 activation, which are activated in macrophages during phagocytosis of apoptotic cells. These results demonstrate that HMGB1 blocks αvβ3-dependent recognition and uptake of apoptotic cells.

The HMGB1 C-terminal tail is responsible for the in vitro and in vivo inhibitory effects of HMGB1 on phagocytosis of apoptotic neutrophils. HMGB1 was described originally as a nuclear protein involved in DNA binding and transcriptional regulation. However, HMGB1 also has an extracellular role as a potent mediator of inflammation and can diminish the uptake of apoptotic cells by phagocytes, a process called efferocytosis. To explore the mechanism responsible for the ability of HMGB1 to inhibit efferocytosis, we examined the role of the C-terminal acidic tail, a region of HMGB1 that has been shown to participate in specific intramolecular interactions. Deletion of the C-terminal tail abrogated the ability of HMGB1 to decrease murine macrophage ingestion of apoptotic neutrophils and to diminish phagocytosis-induced activation of Erk and Rac-1 in macrophages. We found that RAGE plays a major role in efferocytosis, and deletion of the C-terminal tail of HMGB1 prevented binding of HMGB1 to RAGE but not to other macrophage receptors involved in efferocytosis, such as the αVβ3 integrin. Whereas HMGB1 decreased ingestion of apoptotic neutrophils significantly by alveolar macrophages under in vivo conditions in the lungs of mice, this effect was lost when the C-terminal acidic tail was absent from HMGB1. These results demonstrate that the HMGB1 C-terminal tail is responsible for the inhibitory effects of HMGB1 on phagocytosis of apoptotic neutrophils under in vitro and in vivo conditions.

Uncontrolled extracellular matrix production by fibroblasts in response to tissue injury contributes to fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), a progressive and ultimately fatal process that currently has no cure. Although dysregulation of miRNAs is known to be involved in a variety of pathophysiologic processes, the role of miRNAs in fibrotic lung diseases is unclear. In this study, we found up-regulation of miR-21 in the lungs of mice with bleomycin-induced fibrosis and also in the lungs of patients with IPF. Increased miR-21 expression was primarily localized to myofibroblasts. Administration of miR-21 antisense probes diminished the severity of experimental lung fibrosis in mice, even when treatment was started 5–7 d after initiation of pulmonary injury. TGF-β1, a central pathological mediator of fibrotic diseases, enhanced miR-21 expression in primary pulmonary fibroblasts. Increasing miR-21 levels promoted, whereas knocking down miR-21 attenuated, the pro-fibrogenic activity of TGF-β1 in fibroblasts. A potential mechanism for the role of miR-21 in fibrosis is through regulating the expression of an inhibitory Smad, Smad7. These experiments demonstrate an important role for miR-21 in fibrotic lung diseases and also suggest a novel approach using miRNA therapeutics in treating clinically refractory fibrotic diseases, such as IPF.

To determine whether peak systolic velocity of tricuspid annular motion assessed by tissue Doppler echocardiography (Sta), a right ventricular function parameter, can discriminate patients with true- and false-positive pulse pressure variation. Pulse pressure variation is used to predict fluid responsiveness in mechanically ventilated patients. However, this parameter has been reported to be falsely positive, especially in patients with right ventricular dysfunction.A prospective study.Medical and surgical intensive care unit of a university hospital.Thirty- five mechanically ventilated patients hospitalized for24 hrs with a pulse pressure variation of12%.Doppler echocardiography (including measurement of Sta and stroke volume) was performed before and after infusion of 500 mL of colloid solution. Patients were classified into two groups according to their response to fluid infusion: responders (at least 15% increase in stroke volume) and nonresponders.Twenty-three patients (66%) were responders (true-positive group) and 12 (34%) were nonresponders (false-positive group). Before volume expansion, Sta was statistically lower in the nonresponder group (0.13 [0.04] vs. 0.20 [0.05], p = .0004). The area under the curve of the receiver operating characteristic curve was 0.87 (95% confidence interval, 0.74-1). In patients with pulse pressure variation of12%, a Sta cutoff value of 0.15 m/s discriminated between responders and nonresponders with a sensitivity of 91% (80-100) and a specificity of 83% (62-100).A Sta value of0.15 m/s seems to be an accurate parameter to detect false-positive pulse pressure variation. Echocardiography should therefore be performed before fluid infusion in patients with pulse pressure variation of12%.

High-fidelity simulation (HFS) calls heavily upon cognitive capacities and generates stress and anxiety. The objectives of this prospective, observational study were to assess trait anxiety and fear of negative evaluation (FNE) in anaesthesiology and critical care residents and appraise their state anxiety levels and cardiovascular responses during HFS training sessions.First-year anaesthesiology and critical care residents completed the French-Canadian adaptation of the State-Trait Anxiety Inventory (IASTA Y-1: state anxiety, IASTA Y-2: trait anxiety) and the French adaptation of the Fear of Negative Evaluation Scale (FNE). Their heart rate (HR) and blood pressure (BP) were assessed before and after the training session.Twenty-three residents (8 women, 15 men) were included in the study. IASTA Y-1 and Y-2 scores were low (respectively 40.2±9.9 and 39.7±8) and FNE scores were moderate (16.7±5.5). HR measurements before and after the training sessions were significantly higher than at rest (respectively 78±19, 80±17 and 63±9b/min; P0.001). BP measurements before and after the HFS sessions were not significantly different. The IASTA Y-2 and FNE scores of female residents were significantly higher than those of male residents (respectively P=0.004 and P=0.049).First-year anaesthesiology and critical care residents had low trait anxiety and FNE. HFS training increased their HR but not their BP. Their state anxiety also remained low. Several differences between individuals were noted, particularly between men and women.

The description of the systemic inflammatory response syndrome (SIRS) as a reaction to numerous insults marked a turning point in the understanding of acute critical states, which are intensive care basic cases. This concept highlighted the final inflammatory response features whichever the injury mechanism is: infectious, or non-infectious such as extensive burns, traumas, major surgery or acute pancreatitis. In these cases of severe non-infectious insult, many endogenous mediators are released. Like infectious agents components, they can activate the immune system (via common signaling pathways) and initiate an inflammatory response. They are danger signals or alarmins. These molecules generally play an intracellular physiological role and acquire new functions when released in extracellular space. Many progresses brought new information on these molecules and on their function in infectious and non-infectious inflammation. These danger signals can be used as biomarkers and provide new pathophysiological and therapeutic approaches, particularly for immune dysfunctions occurring after an acute injury. We present herein the danger model, the main danger signals and the clinical consequences.