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Background: The mechanisms of organ failure during sepsis are not fully understood. The hypothesis of circulating factors has been suggested to explain septic myocardial dysfunction. We explored the biological coherence of a large panel of sepsis mediators and their clinical relevance in septic myocardial dysfunction and organ failures during human septic shock., Methods: Plasma concentrations of 24 mediators were assessed on the first day of septic shock using a multi-analyte cytokine kit. Septic myocardial dysfunction and organ failures were assessed using left ventricle ejection fraction (LVEF) and the Sequential Organ Failure Assessment score, respectively., Results: Seventy-four patients with septic shock (and without immunosuppression or chronic heart failure) were prospectively included. Twenty-four patients (32%) had septic myocardial dysfunction (as defined by LVEF < 45%) and 30 (41%) died in ICU. Hierarchical clustering identified three main clusters of sepsis mediators, which were clinically meaningful. One cluster involved inflammatory cytokines of innate immunity, most of which were associated with septic myocardial dysfunction, organ failures and death; inflammatory cytokines associated with septic myocardial dysfunction had an additive effect. Another cluster involving adaptive immunity and repair (with IL-17/IFN pathway and VEGF) correlated tightly with a surrogate of early sepsis resolution (lactate clearance) and ICU survival., Conclusions: In this preliminary study, we identified a cluster of cytokines involved in innate inflammatory response associated with septic myocardial dysfunction and organ failures, whereas the IL-17/IFN pathway was associated with a faster sepsis resolution and a better survival.

Background: Pleural effusion is common during invasive mechanical ventilation, but its role during weaning is unclear. We aimed at assessing the prevalence and risk factors for pleural effusion at initiation of weaning. We also assessed its impact on weaning outcomes and its evolution in patients with difficult weaning., Methods: We performed a prospective multicenter study in five intensive care units in France. Two hundred and forty-nine patients were explored using ultrasonography. Presence of moderate-to-large pleural effusion (defined as a maximal interpleural distance ≥ 15 mm) was assessed at weaning start and during difficult weaning., Results: Seventy-three (29%) patients failed weaning, including 46 (18%) who failed the first spontaneous breathing trial (SBT) and 39 (16%) who failed extubation. Moderate-to-large pleural effusion was detected in 81 (33%) patients at weaning start. Moderate-to-large pleural effusion was associated with more failures of the first SBT [27 (33%) vs. 19 (11%), p < 0.001], more weaning failures [37 (47%) vs. 36 (22%), p < 0.001], less ventilator-free days at day 28 [21 (5-24) vs. 23 (16-26), p = 0.01], and a higher mortality at day 28 [14 (17%) vs. 14 (8%), p = 0.04]. The association of pleural effusion with weaning failure persisted in multivariable analysis and sensitivity analyses. Short-term (48 h) fluid balance change was not associated with the evolution of interpleural distance in patients with difficult weaning., Conclusions: In this multicenter observational study, pleural effusion was frequent during the weaning process and was associated with worse weaning outcomes.

Background: Patients meeting the Berlin definition for the acute respiratory distress syndrome (ARDS) might lack exposure to one or more "common" risk factors and exhibit different clinical phenotype and outcomes. We aimed to compare the clinical presentation and outcome of ARDS patients with or without risk factors, the impact on hospital mortality, and to assess the diagnostic work-up performed. The current study is an ancillary analysis of an international, multicenter, prospective cohort study (the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure, LUNG SAFE). Patients meeting ARDS criteria within 2 days of acute hypoxemic respiratory failure onset were included in the study and categorized as having risk factors or not. Outcomes were compared using propensity score matching., Results: Among 2813 patients, 234 (8.3% [7.3-9.3]) had no ARDS risk factor identified. These were older, had more frequent chronic diseases and presented with less severe SOFA and non-pulmonary SOFA scores (p < 0.001). Compared to other ARDS, CT scan (32.1 vs 23.9%, p < 0.001) and open lung biopsy (2.6 vs 0.2%, p < 0.001) were slightly more frequent but left heart filling pressures assessment was not (69.4 vs 68.4%, p > 0.99). Among ARDS with no risk factor, 45 patients (19.2%) had a specific diagnosis made. As compared to others, patients having ARDS with no risk factor had a lower ICU but not hospital mortality (34.6 vs 40.0%; p = 0.12). A matched cohort analysis confirmed the lack of significant difference in mortality., Conclusion: Eight percent of ARDS patients have no identified risk factor, 80% of whom have no etiological diagnosis made. The outcome of ARDS with no risk factor was comparable to other ARDS but few had a comprehensive diagnostic work-up, potentially leading to missed curable diseases. Trial registration clinicaltrials.gov Identifier: NCT02010073.

Background: We assessed prevalence, associated factors and prognosis of extended-spectrum beta-lactamase-producing Enterobacteriaceae pneumonia acquired in intensive care unit (ESBL-PE pneumonia) among carriers. Variables associated with nosocomial pneumonia caused by carbapenem-resistant bacteria (CRB) were also assessed., Methods: A 6-year prospective study (May 2009-March 2015) in the medical ICU of an 850-bed university-affiliated hospital was conducted., Results: Of the 6303 patients admitted, 843 (13.4%) had ESBL-PE carriage detected. Among carriers, 111 (13%) patients developed ICU-acquired pneumonia of whom 48 (43%) had ESBL-PE pneumonia (6% of carriers). By multivariable analysis, SAPS II at admission >43 [OR 2.81 (1.16-6.79)] and colonization with Enterobacter sp. or K. pneumoniae species [OR 10.96 (2.93-41.0)] were independent predictive factors for ESBL-PE pneumonia in colonized patients, whereas receipt of >2 days of amoxicillin/clavulanic acid during the ICU stay [OR 0.24 (0.08-0.71)] was protective. Patients with ESBL-PE pneumonia had a higher SOFA score (p = 0.037) and more frequent septic shock at pneumonia onset (p = 0.047). However, ESBL-PE pneumonia was not an independent predictor of mortality. Twenty-five patients had pneumonia caused by CRB. Chronic renal insufficiency, administration of third-generation cephalosporin within the past 3 months, acute respiratory distress syndrome before pneumonia and prior therapy with a carbapenem or fluoroquinolones were associated with CRB pneumonia in this selected population., Conclusions: Although few ESBL-PE carriers developed ESBL-PE pneumonia overall, a high proportion of pneumonia were caused by ESBL-PE in carriers developing ICUAP. ESBL-PE pneumonia was not an independent predictor of mortality. As pneumonia caused by CRB is increasing, knowledge of factors associated with ESBL-PE or CRB pneumonia may help empiric therapy of pneumonia among ESBL-PE carriers.

Several studies suggest that alternatives to carbapenems, and particulary beta-lactam/beta-lactamase inhibitor combinations, can be used for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE)-related infections in non-ICU patients. Little is known concerning ICU patients in whom achieving the desired plasmatic pharmacokinetic/pharmacodynamic (PK/PD) target may be difficult. Also, in vitro susceptibility to beta-lactamase inhibitors might not translate into clinical efficacy. We reviewed the recent clinical studies examining the use of BL/BLI as alternatives to carbapenems for therapy of bloodstream infection, PK/PD data and discuss potential ecological benefit from avoiding the use of carbapenems. With the lack of prospective randomized studies, treating ICU patients with ESBL-PE-related infections using piperacillin-tazobactam should be done with caution. Current data suggest that BL/BLI empirical use should be avoided for therapy of ESBL-PE-related infection. Also, definitive therapy should be reserved to patients in clinical stable condition, after microbial documentation and results of susceptibility tests. Optimization of administration and higher dosage should be used in order to reach pharmacological targets.

Background: The detection of Aspergillus spp. in endotracheal aspirate cultures of mechanically ventilated patients may reflect either colonization or infection. However, little is known about the prevalence and the impact on outcome of respiratory tract sample positive for Aspergillus during the acute respiratory distress syndrome (ARDS)., Methods: We conducted a monocentric, retrospective study over a 10-year period (January 2006-December 2015) in the ICU of a university hospital. All consecutive adult patients with ARDS were included, and the diagnosis of invasive pulmonary aspergillosis was assessed using a previously validated algorithm., Results: In total, 423 ARDS patients were included with 35 patients [8.3 %, 95 % CI (5.4-10.6)] having at least one respiratory tract sample positive for Aspergillus (Aspergillus(+) patients) after a median delay of 3 days (1-11) following ICU admission. Comorbidities did not differ between Aspergillus(+) and Aspergillus(-) patients except for more frequent immunosuppression in Aspergillus(+) patients (40 vs. 22 %; p = 0.02). There was no difference between Aspergillus(-) and Aspergillus(+) patients regarding in-ICU mortality, ventilator-free days at day 28, and incidence of ventilator-associated pneumonia, but need for renal replacement therapy was higher in Aspergillus(+) patients than in others (49 vs. 27 %; p = 0.01). Seventeen [4.0 %, 95 % CI (2.1-5.9)] patients had putative/proven aspergillosis. After adjusting on covariates associated with ICU mortality, putative/proven aspergillosis was associated with in-ICU mortality [aOR = 9.58 (1.97-46.52); p = 0.005], while Aspergillus colonization was not [aOR = 0.64 (0.21-1.99); p = 0.44]., Conclusions: Eight percent of ARDS patients had Aspergillus spp.-positive respiratory tract cultures. These had a higher risk of mortality only when categorized as having putative or proven invasive pulmonary aspergillosis.

Background: The aims of this study were to prospectively assess the prevalence of sustained (lasting more than 30 s) new-onset supraventricular arrhythmia (NOSVA) during septic shock, identify the associated factors (including septic myocardial dysfunction), and evaluate its impact on hemodynamics and prognosis., Methods: Patients with a diagnosis of septic shock were screened in a medical intensive care unit of a tertiary hospital center in France with a continuous 12-lead EKG for the occurrence of NOSVA. Biological and clinical data (including septic myocardial dysfunction characterized by echocardiography) were collected. We also assessed the hemodynamic tolerance and prognosis of NOSVA., Results: Among the 71 septic shock episodes assessed during the study, NOSVA occurred in 30 [prevalence of 42 %, 95 % confidence interval (CI) 30-53 %]. Among all recorded factors, only renal failure (as assessed by renal SOFA score at day 1) was associated with NOSVA and this difference persisted by multivariable analysis (odds ratio of 1.29, 95 % CI 1.03-1.62, p = 0.03). There was a significant increase in norepinephrine dosage during the first hour after SVA onset. NOSVA was associated with longer catecholamine use during septic shock as compared with patients in sinus rhythm, whereas ICU mortality was identical between groups., Conclusions: We found a high prevalence of sustained NOSVA during septic shock. NOSVA was not related to septic myocardial dysfunction, but rather to acute renal failure, raising the hypothesis of an acute renocardiac syndrome.

Background: Patients with severe cardiogenic pulmonary edema (CPE) are frequently hypercapnic, possibly because of associated underlying chronic lung disease (CLD). Since hypercapnia has been associated with outcome, we aimed to identify factors associated to hypercapnia and its role on outcome of patients with CPE and no underlying CLD., Methods: Observational cohort study using data prospectively collected over a 3-year period. After excluding patients with any CLD or obstructive sleep apneas, all patients treated by non-invasive ventilation (NIV) for severe CPE were included. Hypercapnia was defined as PaCO2 >45 mmHg and non-rapid favorable outcome was defined as the need for intubation or continuation of NIV for more than 48 h., Results: After excluding 60 patients with underlying CLD or sleep apneas, 112 patients were studied. The rates of intubation and of prolonged NIV were 6.3 % (n = 7) and 21.4 % (n = 24), respectively. Half of the patients (n = 56) had hypercapnia upon admission. Hypercapnic patients were older, more frequently obese, and were more likely to have a respiratory tract infection than non-hypercapnic patients. Hypercapnia had no influence on intubation rate or the need for prolonged NIV. However, patients with severe hypercapnia (PaCO2 >60 mmHg) needed longer durations of NIV and intensive care unit (ICU) stay than the others., Conclusions: Among the patients admitted for severe CPE without CLD, half of them had hypercapnia at admission. Hypercapnic patients were older and more frequently obese but their outcome was similar compared to non-hypercapnic patients. Patients with severe hypercapnia needed longer durations of NIV than the others without increase in intubation rate.

Background: Transpulmonary bubble transit (TPBT) detected with contrast echocardiography is reported as a sign of intrapulmonary shunt during cirrhosis or exercise in healthy humans. However, its physiological meaning is not clear during acute respiratory distress syndrome (ARDS). Our aim was to determine the prevalence, significance, and prognosis of TPBT detection during ARDS., Methods: This was a prospective observational study in an academic medical intensive care unit in France. Two hundred and sixteen consecutive patients with moderate-to-severe ARDS underwent transesophageal echocardiography with modified gelatine contrast. Moderate-to-large TPBT was defined as right-to-left passage of at least ten bubbles through a pulmonary vein more than three cardiac cycles after complete opacification of the right atrium. Patients with intra-cardiac shunt through patent foramen ovale were excluded., Results: The prevalence of moderate-to-large TPBT was 26% (including 42 patients with moderate and 15 with large TPBT). Patients with moderate-to-large TPBT had higher values of cardiac index and heart rate as compared to those without TPBT. There was no significant difference in PaO2/FIO2 ratio between groups, and TPBT was not influenced by end-expiratory positive pressure level in 93% of tested patients. Prevalence of septic shock was higher in the group with moderate-to-large TPBT. Patients with moderate-to-large TPBT had fewer ventilator-free days and intensive care unit-free days within the first 28 days, and higher in-hospital mortality as compared to others., Conclusions: Moderate-to-large TPBT was detected with contrast echocardiography in 26% of patients with ARDS. This finding was associated with a hyperdynamic and septic state, but did not influence oxygenation.

In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, suPAR, ProADM, and Presepsin. New approaches to biomarkers of infections include point-of-care testing and genomics.

Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest®; a single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has been obtained. For ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is < 0.5 ng/mL or has decreased by >80% relative to the highest level recorded, irrespective of the severity of the infectious episode; in bacteremic patients, a minimal duration of therapy of 5 days is recommended.