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Additional file 1. Additional figures and table.

Supplemental Digital Content is available in the text., Objectives: As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function, the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass. Design: Randomized controlled trial. Setting: Tertiary mixed ICU. Patients: Adult patients admitted for septic shock within the first 72 hours. Interventions: Patients were assigned randomly into two groups. The control group benefited from manual mobilization once a day. The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy. Measurements and Main Results: Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7. Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers. Hemodynamic values and patient perception were collected during each session. Twenty-one patients were included. Three died before the second muscle biopsy. Ten patients in the control and eight in the intervention group were analyzed. Markers of the catabolic ubiquitin-proteasome pathway, muscle atrophy F-box and muscle ring finger-1 messenger RNA, were reduced at day 7 only in the intervention group, but without difference between groups (muscle atrophy F-box: –7.3% ± 138.4% in control vs –56.4% ± 37.4% in intervention group; p = 0.23 and muscle ring finger-1: –30.8% ± 66.9% in control vs –62.7% ± 45.5% in intervention group; p = 0.15). Muscle fiber cross-sectional area (µm2) was preserved by exercise (–25.8% ± 21.6% in control vs 12.4% ± 22.5% in intervention group; p = 0.005). Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group, without being suppressed. Markers of anabolism and inflammation were not modified by the intervention, which was well tolerated by the patients. Conclusions: Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area.

OBJECTIVES: Approximately half of the patients undergoing lung biopsy for nonresolving acute respiratory distress syndrome exhibit another histologic pattern than diffuse alveolar damage, with some of the pathologies characterized by a potential response to corticosteroids. This study aimed to assess whether open lung biopsy performed in the ICU for nonresolving acute respiratory distress syndrome was able to identify steroid-sensitive diseases and whether patients with a steroid-sensitive pathology experienced different clinical courses and outcomes. DESIGN: Retrospective analysis. SETTING: One 22-bed mixed ICU within a tertiary medical center. PATIENTS: Patients age greater than or equal to 16 years old who met the Berlin definition for acute respiratory distress syndrome and underwent open lung biopsy from January 2007 to January 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 695 patients diagnosed with acute respiratory distress syndrome were identified, 51 (7%) of whom underwent open lung biopsy. An alternative diagnosis to diffuse alveolar damage was found in 29 patients (57%), and a steroid-sensitive pathology was identified in 19 (37%). In-hospital and 180-day mortality rates were 55% and 61%, respectively. There was a significant difference in hospital mortality and 180-day mortality rates between patients with steroid-sensitive pathology and those with steroid-resistant pathology (37% vs 65%; p < 0.045 and 37% vs 75%; p < 0.007, respectively). We did not identify any variable that could reliably predict a steroid-sensitive histologic pattern before open lung biopsy. CONCLUSIONS: Open lung biopsy was able to identify a steroid-sensitive pathology in a significant proportion of nonresolving acute respiratory distress syndrome patients. These patients had a better outcome, with lower hospital mortality and 180-day mortality.

International audience; Purpose: Acute kidney injury (AKI) is associated with the activation of the renin–angiotensin system. Whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) improve outcome in patients recovering from AKI remains unexplored. The purpose was to investigate the association between prescription of ACEi/ARB at intensive care unit (ICU) discharge and 1-year outcome in patients recovering from AKI.Methods: Association between ACEi/ARB and 1-year mortality rate was explored in 1551 patients discharged from 21 European ICUs in an observational cohort. One-year all-cause mortality after ICU discharge was the primary endpoint. AKI was defined using the kidney disease improvement global outcome definition. Propensity score matching was used to consider the probability to receive ACEi/ARB at ICU discharge and included chronic heart failure, ACEi/ARB on ICU admission, Charlson Comorbidity Index, age, diabetes mellitus, chronic kidney disease, estimated glomerular filtration rate and arterial blood pressure at ICU discharge vasopressors and renal replacement therapy.Results: Overall, 1-year mortality was 28 and 15% in patients with AKI (n = 611, 39%) and without AKI (n = 940), respectively. In patients with AKI, unadjusted, adjusted and propensity-score matched 1-year mortality rates were lower in patients treated with ACEi/ARB at ICU discharge [HR of 0.55 (0.35–0.89), HR of 0.45 (0.27–0.75), and HR of 0.48 (0.27–0.85, p

Septic shock carries substantial morbidity and mortality. The failure of many promising therapies during late-phase clinical trials prompted calls for alternative trial designs. We describe an innovative trial evaluating selepressin, a novel selective vasopressin V1a receptor agonist, for adults with septic shock. SEPSIS-ACT (Selepressin Evaluation Programme for Sepsis-induced Shock—Adaptive Clinical Trial) is a blinded, randomized, placebo-controlled, two-part, adaptive phase 2b/3 trial, evaluating up to four selepressin dosing strategies. The primary outcome is pressor- and ventilator-free days, with a value of zero assigned for death within 30 days. We calculate Bayesian probabilities of final trial success to guide interim decision-making. Part 1 (dose-finding) has an adaptive sample size based on response-adaptive randomization and prespecified rules to determine stopping for futility or selection of the best dosing regimen for Part 2. Part 2 (confirmation) randomizes a minimum of 1,000 patients equa...

IntroductionSepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock.MethodsThe Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.ResultsMedian age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median= 65 [IQR= 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P< 0.0001), also after adjustment for confounding factors (adjusted odds ratio= 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P&nbsp

Repaglinide is a short-acting insulin secretagogue used for the reduction in postprandial glucose levels in diabetic patients. It has a favorable safety profile with a low risk of hypoglycemia. Prolonged hypoglycemia appears exceptional due to the short serum elimination half-life. [...]

Background This systematic review aimed to assess inhaled drug delivery in mechanically ventilated patients or in animal models. Whole lung and regional deposition and the impact of the ventilator circuit, the artificial airways and the administration technique for aerosol delivery were analyzed. Methods In vivo studies assessing lung deposition during invasive mechanical ventilation were selected based on a systematic search among four databases. Two investigators independently assessed the eligibility and the risk of bias. Results Twenty-six clinical and ten experimental studies were included. Between 30% and 43% of nominal drug dose was lost to the circuit in ventilated patients. Whole lung deposition of up to 16% and 38% of nominal dose (proportion of drug charged in the device) were reported with nebulizers and metered-dose inhalers, respectively. A penetration index inferior to 1 observed in scintigraphic studies indicated major proximal deposition. However, substantial concentrations of antibiotics were measured in the epithelial lining fluid (887 (406–12,819) μg/mL of amikacin) of infected patients and in sub-pleural specimens (e.g., 197 μg/g of amikacin) dissected from infected piglets, suggesting a significant distal deposition. The administration technique varied among studies and may explain a degree of the variability of deposition that was observed. Conclusions Lung deposition was lower than 20% of nominal dose delivered with nebulizers and mostly occurred in proximal airways. Further studies are needed to link substantial concentrations of antibiotics in infected pulmonary fluids to pulmonary deposition. The administration technique with nebulizers should be improved in ventilated patients in order to ensure an efficient but safe, feasible and reproducible technique. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1844-5) contains supplementary material, which is available to authorized users.

OBJECTIVES: Adrenomedullin has vascular properties and elevated plasma adrenomedullin levels were detected in sepsis. We assessed, in septic and nonseptic ICU patients, the relation between circulating adrenomedullin, the need for organ support and mortality, using an assay of bioactive adrenomedullin. DESIGN: Prospective multicenter observational cohort study. SETTING: Data from the French and euRopean Outcome reGistry in ICUs study. PATIENTS: Consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 hours following ICU admission and discharged from ICU were included. INTERVENTIONS: Clinical and biological parameters were collected at baseline, including bioactive-adrenomedullin. Status of ICU survivors was assess until 1 year after discharge. The main outcome was the need for organ support, including renal replacement therapy and/or for inotrope(s) and/or vasopressor(s). Secondary endpoints were the ICU length of stay and the 28-day all-cause mortality. MEASUREMENTS AND MAIN RESULTS: Median plasma bioactive adrenomedullin (n = 2,003) was 66.6 pg/mL (34.6-136.4 pg/mL) and the median Simplified Acute Physiology Score II score 49 (36-63). Renal replacement therapy was needed in 23% and inotropes(s) and/or vasopressor(s) in 77% of studied patients. ICU length of stay was 13 days (7-21 d) and mortality at 28 days was 22 %. Elevated bioactive adrenomedullin independently predicted 1) the need for organ support (odds ratio, 4.02; 95% CI, 3.08-5.25) in ICU patients whether admitted for septic or nonseptic causes and 2) the need for renal replacement therapy (odds ratio, 4.89; 3.83-6.28), and for inotrope(s) and/or vasopressor(s) (odds ratio, 3.64; 2.84-4.69), even in patients who were not on those supports at baseline. Elevated bioactive adrenomedullin was also associated with a prolonged length of stay (odds ratio, 1.85; 1.49-2.29) and, after adjustment for Simplified Acute Physiology Score II, with mortality (odds ratio, 2.31; 1.83-2.92). CONCLUSIONS: Early measurement of bioactive adrenomedullin is a strong predictor of the need of organ support and of short-term mortality in critically ill patients

Cirrhosis is a serious and life-threatening condition which imposes a significant socioeconomic burden on affected individuals and healthcare systems. Cirrhosis can result in portal hypertension, which may lead to major complications, including acute variceal bleeding and hepatorenal syndrome. Without prompt treatment, these complications may be life-threatening. Over the past 2 decades, new treatment modalities and treatment strategies have been introduced, which have improved patients' prognosis, but the initial management of these severe complications continues to present a challenge. The present recommendations aim to increase clinicians' knowledge on the importance of early diagnosis and treatment, and to provide evidence-based management strategies to potentially, further improve patient outcomes. Special attention was given to the role of terlipressin. A comprehensive non-systematic literature search was undertaken to evaluate the evidence for the diagnosis and initial management of acute variceal bleeding and hepatorenal syndrome in patients with cirrhosis. Recommendations on the diagnosis and initial management of acute variceal bleeding and hepatorenal syndrome in patients with cirrhosis have been developed based on the best available evidence and the expert opinion of the consensus panel following a comprehensive review of the available clinical data. Prompt identification and timely treatment of acute variceal bleeding and hepatorenal syndrome are essential to reduce the burden. ispartof: DIGESTIVE DISEASES AND SCIENCES vol:64 issue:6 pages:1419-1431 ispartof: location:United States status: published

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

The case is reported of a 39-year-old severely obese woman who developed acute metabolic disorders after the administration of a short course of intravenous amiodarone. The main biological features were hypertriglyceridemia, hypoglycaemia, hyperlactatemia and hyperammonemia; all were reversible after amiodarone discontinuation. There was an associated rise in liver enzymes. However, the influence of co-factors on these metabolic disorders, such as acquired carnitine deficiency, severe obesity, a long-term course of pancreatitis, and abdominal infections, could not be excluded.

Liver transplantation is the treatment for end-stage liver diseases and well-selected malignancies. The allograft shortage may be alleviated with living donation. The initial UCLouvain experience of adult living-donor liver transplantation (LDLT) is presented. A retrospective analysis of 64 adult-to-adult LDLTs performed at our institution between 1998 and 2016 was conducted. The median age of 29 (45.3%) females and 35 (54.7%) males was 50.2 years (interquartile range, IQR 32.9-57.5). Twenty-two (34.4%) recipients had no portal hypertension. Three (4.7%) patients had a benign and 33 (51.6%) a malignant tumor [19 (29.7%) hepatocellular cancer, 11 (17.2%) secondary cancer and one (1.6%) each hemangioendothelioma, hepatoblastoma and embryonal liver sarcoma]. Median donor and recipient follow-ups were 93 months (IQR 41-159) and 39 months (22-91), respectively. Right and left hemi-livers were implanted in 39 (60.9%) and 25 (39.1%) cases, respectively. Median weights of right- and left-liver were 810 g (IQR 730-940) and 454 g (IQR 394-534), respectively. Graft-to-recipient weight ratios (GRWRs) were 1.17% (right, IQR 0.98%-1.4%) and 0.77% (left, 0.59%-0.95%). One- and five-year patient survivals were 85% and 71% (right) vs. 84% and 58% (left), respectively. One- and five-year graft survivals were 74% and 61% (right) vs. 76% and 53% (left), respectively. The patient and graft survival of right and left grafts and of very small (

INTRODUCTION: Impairment of global and regional pulmonary ventilations is a well-known consequence of general anesthesia. Positive expiratory pressure (PEP) or incentive spirometry (IS) is commonly prescribed, albeit their efficacy is poorly demonstrated. The aim of this study was to assess the effects of PEP and IS on lung ventilation and recruitment in patients after surgery involving anesthesia using electrical impedance tomography (EIT). METHOD: Ten male subjects (age = 61.2 ± 16.3 years; BMI = 25.3 ± 3.8 kg/m2), free of pulmonary disease before being anesthetized, were recruited. Two series of manoeuvers (PEP and volume-oriented IS) were randomly performed with quiet breathing interposed between these phases. Pulmonary ventilation (ΔEELVVT (i - e)) and recruitment (ΔEELI) were evaluated continuously in a semi-seated position during all phases by EIT. Comparisons between rest and treatment were performed by Wilcoxon signed rank test. Rest phases were compared by a mixed ANOVA. Bonferroni method was used for post-hoc comparisons. RESULTS: ΔEELVVT (i - e) and ΔEELI were significantly increased by both techniques (+422% [p < 0.001]; +138% [p = 0.040] and +296% [p < 0.001]; +638% [p < 0.001] for PEP and IS, respectively). No difference was observed between both manoeuvers neither on ventilation nor on recruitment. This positive effect disappeared during the quiet breathing phases. CONCLUSION: IS and PEP improved ventilation and recruitment instantaneously without remnant effect after stopping the exercise.

Sir, Resistance of Gram-negative pathogens to current antibiotics has revived interest in earlier and often disused molecules for which resistance is still low. Yet, detailed pharmacokinetic/pharmacodynamic data are scarce for these drugs. A typical example is temocillin (6-α-methoxy-ticarcillin), active against most Gram-negative bacteria, which shows stability against a variety of β-lactamases, including most ESBLs, AmpC and some carbapenemases. Temocillin represents a strategic sparing alternative to carbapenems.1 There is no EUCAST breakpoint set for temocillin, but in recent surveys, MIC90 values of 8–16 mg/L were reported for ESBL and AmpC producers [...]

BMJ open 9(2), e024475 (2019). doi:10.1136/bmjopen-2018-024475, Published by BMJ Publishing Group, London

Summary Background Severe community-acquired pneumonia caused by Streptococcus pneumoniae is associated with high morbidity and mortality rates. CAL02, a novel antitoxin agent with an unprecedented mode of action, consists of liposomes that capture bacterial toxins known to dysregulate inflammation, cause organ damage, and impede immune defence. We aimed to assess the safety of CAL02 as an add-on therapy to antibiotics. Methods This randomised, double-blind, multicentre, placebo-controlled trial was done in ten intensive care units (ICUs) in France and Belgium (but only six units enrolled patients), in patients with severe community-acquired pneumococcal pneumonia who required ICU admission and had been identified as being infected with S pneumoniae. We randomly assigned participants in two stages—the first stage randomly assigned six patients (1:1) to either low-dose CAL02 or placebo, and the second stage randomly assigned 18 patients (14:4) to either high-dose CAL02 or placebo, and stratified in four blocks (4:1, 4:1, 3:1, and 3:1), in addition to standard of care. Block randomisation was done with a computer-generated random number list. Participants, investigators, other site study personnel, the sponsor, and the sponsor's designees involved in study management and monitoring were masked to the randomisation list and treatment assignment. Patients were treated with low-dose (4 mg/kg) or high-dose (16 mg/kg) CAL02 or placebo (saline), in addition to standard antibiotic therapy. Two intravenous doses of study treatment were infused, with a 24 h interval, at a concentration of 10 mg/mL, stepwise, over a maximum of 2 h on days 1 and 2. The primary objective of the study was to assess the safety and tolerability of low-dose and high-dose CAL02 in patients with severe community-acquired pneumonia treated with standard antibiotic therapy, and the primary analysis was done on the safety population (all patients who received at least one dose of the study treatment). Efficacy was a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02583373. Findings Between March 21, 2016, and Jan 13, 2018, we screened 280 patients with community-acquired pneumonia. 19 patients were enrolled and randomly assigned, resulting in 13 patients in the CAL02 groups (three assigned to low-dose CAL02 and ten assigned to high-dose CAL02) and six in the placebo group. One patient randomly assigned to placebo was allocated to the wrong treatment group and received high-dose CAL02 instead of placebo. Thus, 14 patients received CAL02 (three received low-dose CAL02 and 11 received high-dose CAL02) and five patients received placebo, constituting the safety population. At baseline, the mean APACHE II score for the total study population was 21·5 (SD 4·9; 95% CI 19·3–23·7) and 11 (58%) of 19 patients had septic shock. Adverse events occurred in 12 (86%) of 14 patients in the CAL02 treatment groups combined and all five (100%) patients in the placebo group. Serious adverse events occurred in four (29%) of 14 patients in the CAL02 treatment groups combined and two (40%) of five patients in the placebo group. One non-serious adverse event (mild increase in triglycerides) in a patient in the high-dose CAL02 group was reported as related to study drug. However, analysis of the changes in triglyceride levels in the CAL02 groups compared with the placebo group revealed no correlation with administration of CAL02. No adverse events were linked to local tolerability events. All patients, apart from one who died in the low CAL02 group (death not related to the study drug) achieved clinical cure at the test of cure visit between days 15 and 22. The sequential organ failure assessment score decreased by mean 65·0% (95% CI 50·7–79·4) in the combined CAL02 groups compared with 29·2% (12·8–45·5) in the placebo group between baseline and day 8. Interpretation The nature of adverse events was consistent with the profile of the study population and CAL02 showed a promising safety profile and tolerability. However, the difference between high-dose and low-dose CAL02 could not be assessed in this study. Efficacy was in line with the expected benefits of neutralising toxins. The results of this study support further clinical development of CAL02 and provide a solid basis for a larger clinical study. Funding Combioxin.

1. The Pro position : The SCARLET study (Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin) required a herculean effort spanning over 6 years from 159 investigative sites across 26 countries to finish this phase 3 trial, testing a recombinant human form of soluble thrombomodulin in sepsis/septic shock [1]. A total of 800 patients were randomised in this double-blind, placebo-controlled trial. Looking on the bright side, this study confirms that soluble thrombomodulin has an excellent safety record in treating septic patients. This adds further evidence of a low incidence of serious bleeding events or other possible toxicities found in safety studies performed in Japan, where soluble thrombomodulin is already available on the market as a treatment for disseminated intravascular coagulation from sepsis-induced coagulopathy [...]

Introduction Host immune response to the coronavirus disease 2019 (COVID-19) is variable and can induce a dysregulated inflammatory response associated with venous and arterial thrombosis called COVID-19 associated coagulopathy (CAC). During septic shock, inflammatory reaction generates endothelial activation and procoagulant state with microvascular thrombi inducing disseminated intravascular coagulation (DIC). Although CAC and DIC induce altered coagulation responses, their clinical outcomes are different. Objective We investigated and compared coagulopathy between septic shock and critical COVID-19 patients. Method Septic shock patients were diagnosed following the Survival Sepsis Campaign guidelines. COVID-19 patients were admitted in intensive care unit (ICU) for severe acute respiratory distress syndrome. Both were included in the study within 2 days after admission. Biomarkers were measured by ELISA from patient's plasma. Results We observed an increase in vWF and TFPI in both septic and COVID-19 patients compared to controls, highlighting endothelial damage. Interestingly, circulating TF was only elevated in COVID-19 patients. Platelet activation differed between the two cohorts of patients. P-selectin and TLT-1 were specifically heightened in septic shock whereas CD40L was only augmented in COVID-19. Coagulation markers were increased in a disease-dependent way, with PAI-1, tPA and D-Dimers higher in septic shock and fibrinogen level, higher in COVID-19. Discussion COVID-19 patients had longer length-of-stay with more pronounced respiratory failure. This strong lung disruption overtime induced plasmatic TF release with sustained inflammatory response characterized by sCD40L and fibrinogen secretion. Given the similarities between COVID-19 and septic shock regarding fibrinolysis and coagulation, but not platelet activation, endothelium seems to play a central role in COVID-19 and might explain the differences between CAC and DIC.

To evaluate the outcome of pediatric living donor liver transplantation (LDLT) regarding portal vein (PV) reconstruction, ABO compatibility, and impact of maternal donation on graft acceptance.LDLT and ABO-mismatched transplantation constitute feasible options to alleviate organ shortage in children. Vascular complications of portal hypoplasia in biliary atresia (BA) and acute rejection (AR) are still major concerns in this field.Data from 250 pediatric LDLT recipients, performed at Cliniques Universitaires Saint-Luc between July 1993 and June 2012, were collected retrospectively. Results were analyzed according to ABO matching and PV complications. Uni- and multivariate analyses were performed to study the impact of immunosuppression, sex matching, and maternal donation on AR rate.Overall, the 10-year patient survival rate was 93.2%. Neither patient or graft loss nor vascular rejection, nor hemolysis, was encountered in the ABO nonidentical patients (n = 58), provided pretransplant levels of relevant isoagglutinins were below 1/16. In BA recipients, the rate of PV complications was lower after portoplasty (4.6%) than after truncal PV anastomosis (9.8%) and to jump graft interposition (26.9%; P = 0.027). In parental donation, maternal grafts were associated with higher 1-year AR-free survival (55.2%) than paternal grafts (39.8%; P = 0.041), but only in BA patients.LDLT, including ABO-mismatched transplantation, constitutes a safe and efficient therapy for liver failure in children. In BA patients with PV hypoplasia, portoplasty seems to constitute the best technique for PV reconstruction. Maternal donation might be a protective factor for AR.

Optimal loading doses of β-lactams to rapidly achieve adequate drug concentrations in critically ill patients are unknown. This was a post-hoc analysis of a prospective study that evaluated broad-spectrum β-lactams [piperacillin (PIP), ceftazidime (CAZ), cefepime (FEP) and meropenem (MEM)] pharmacokinetics (PKs) in patients with sepsis or septic shock (n = 88). Monte Carlo simulation was performed for 1000 virtual patients using specific sets of covariates for various dosing regimens and different durations of administration. Pharmacodynamic (PD) targets were considered as drug concentrations exceeding at least 50% of time above four times the minimum inhibitory concentration (T>4 × MIC) of Pseudomonas aeruginosa, according to EUCAST criteria, for PIP, 70%T>4 × MIC for CAZ and FEP and 40%T>4 × MIC for MEM. The probability of target attainment (PTA) was derived by calculating the percentage of patients who attained the PK/PD target at each MIC. The optimal loading dose was defined as the one associated with a ≥90% probability to achieve the PD targets. Our simulation model identified an optimal loading dose for PIP of 8 g given as a 3-h infusion (PTA of 96.2%), for CAZ and FEP of 4 g given as a 3-h infusion (PTA of 96.5% and 98.4%, respectively), and for MEM of 2 g given as a 30-min infusion (PTA of 93.4%), with the following antibiotic dose administered 6 h thereafter regardless of the drug. A higher first dose of broad-spectrum β-lactams should be given to adequately treat less-susceptible pathogens in septic patients. These findings need to be validated in a prospective study.

Cytokine storm–mediated organ injury continues to dominate current thinking as the primary mechanism for coronavirus disease 2019 (COVID-19). Although there is an initial hyper-inflammatory phase, mounting evidence suggests that virus-induced defective host immunity may be the real cause of death in many patients.1,2 COVID-19 has been called a serial lymphocyte killer because profound and protracted lymphopenia is a near uniform finding among patients with severe COVID-19 and correlates with morbidity and mortality.1,3 Autopsies demonstrate a devastating depletion of lymphocytes in the spleen and other organs.2 CD4, CD8, and natural killer cells, which play important antiviral roles, are depleted and have reduced function, leading to immune collapse.1 Clinical and pathological findings in patients with COVID-19 indicate that immunosuppression is a critical determinant of outcomes. Secondary hospital-acquired infections occur in 50% of patients who die.1 Cell inclusion bodies, consistent with viral persistence, have been found in lungs, kidneys, and other organs.1,2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific quantitative polymerase chain reaction has revealed viral load in the lungs of most patients at autopsy, consistent with an inability to eliminate the pathogen.1,2 Collectively, these studies indicate that impaired immune competence is an important pathogenic mechanism in COVID-19. Interleukin 7 (IL-7) is a pleiotropic cytokine essential for lymphocyte survival and expansion.4,5 Administration of IL-7 invariably increases circulating and tissue lymphocytes and has been administered to more than 450 patients with an excellent safety profile.4,5 IL-7 is currently in multiple randomized clinical trials for oncologic and infectious disorders, and a trial in the United Kingdom is evaluating its use among patients with severe COVID-19. Importantly, IL-7 has documented efficacy as an antiviral agent.4,5 IL-7 therapy has been shown to restore lymphocyte counts and functional activity, leading to decreased viral load and clinical improvement in several life-threating viral infections.4,5 It has been shown to increase CD4 and CD8 T-cells 3-fold, to improve T-cell activation, to not increase proinflammatory cytokines, and to be well tolerated in patients with bacterial sepsis.6 Thus, a compelling scientific rationale exists for examining whether IL-7 is associated with restored host protective immunity in patients with COVID-19 and immunosuppression and improve outcomes.1

The original version of this article unfortunately contained a mistake. There was a typographical error in Figure 1: “Nebulization time ≤ 30 min” (first light blue square) should be replaced by “Nebulization time ≤ 90 min”. The authors apologize for the mistake.

Background Although oversedation has been associated with increased morbidity in ventilated critically ill patients, it is unclear whether prevention of oversedation improves mortality. We aimed to assess 90-day mortality in patients receiving a bundle of interventions to prevent oversedation as compared to usual care. Methods In this randomized multicentre trial, all adult patients requiring mechanical ventilation for more than 48 h were included. Two groups were compared: patients managed according to usual sedation practices (control), and patients receiving sedation according to an algorithm which provided a gradual multilevel response to pain, agitation, and ventilator dyssynchrony with no specific target to alter consciousness and no use of sedation scale and promoted the use of alternatives to continuous infusion of midazolam or propofol (intervention). Results Inclusions were stopped before reaching the planned enrolment. Between 2012 and 2014, 584 patients were included in the intervention group and 590 in the control group. Baseline characteristics were well balanced between groups. Although the use of midazolam and propofol was significantly lower in the intervention group, 90-day mortality was not significantly lower (39.4 vs. 44.2% in the control group, p = 0.09). There were no significant differences in 1-year mortality between the two groups. The time to first spontaneous breathing trial and time to successful extubation were significantly shorter in the intervention group than in the control group. These last results should be interpreted with precaution regarding the several limitations of the trial including the early termination. Conclusions This underpowered study of severely ill patients was unable to show that a strategy to prevent oversedation could significantly reduce mortality. Trial registration NCT01617265

Purpose: To determine if, compared to pressure support (PS), neurally adjusted ventilatory assist (NAVA) reduces patient-ventilator asynchrony in intensive care patients undergoing noninvasive ventilation with an oronasal face mask. Methods: In this prospective interventional study we compared patient-ventilator synchrony between PS (with ventilator settings determined by the clinician) and NAVA (with the level set so as to obtain the same maximal airway pressure as in PS). Two 20-min recordings of airway pressure, flow and electrical activity of the diaphragm during PS and NAVA were acquired in a randomized order. Trigger delay (T d), the patient's neural inspiratory time (T in), ventilator pressurization duration (T iv), inspiratory time in excess (T iex), number of asynchrony events per minute and asynchrony index (AI) were determined. Results: The study included 13 patients, six with COPD, and two with mixed pulmonary disease. T d was reduced with NAVA: median 35ms (IQR 31-53ms) versus 181ms (122-208ms); p=0.0002. NAVA reduced both premature and delayed cyclings in the majority of patients, but not the median T iex value. The total number of asynchrony events tended to be reduced with NAVA: 1.0events/min (0.5-3.1events/min) versus 4.4events/min (0.9-12.1events/min); p=0.08. AI was lower with NAVA: 4.9 % (2.5-10.5 %) versus 15.8 % (5.5-49.6 %); p=0.03. During NAVA, there were no ineffective efforts, or late or premature cyclings. PaO2 and PaCO2 were not different between ventilatory modes. Conclusion: Compared to PS, NAVA improved patient ventilator synchrony during noninvasive ventilation by reducing T d and AI. Moreover, with NAVA, ineffective efforts, and late and premature cyclings were absent

Acute paracetamol poisoning due to a single overdose may be effectively treated by the early administration of N-acetylcysteine (NAC) as an antidote. The prognosis may be different in the case of intoxication due to multiple ingestions or when the antidote is started with delay. The aim of this work was to investigate the outcome of paracetamol poisoning according to the pattern of ingestion and determine the factors associated with the outcome. We performed a retrospective analysis over the period 2007&ndash, 2017 of the patients who were referred to a tertiary hospital for paracetamol-related hepatotoxicity. Inclusion criteria were: accidental or voluntary ingestion of paracetamol, delay for NAC therapy of 12 h or more, liver enzymes (ALT) &gt, 1000 IU/L on admission. Ninety patients were considered. Poisoned patients following multiple ingestion were significantly older (45 &plusmn, 12 vs. 33 &plusmn, 14) (p = 0.001), with a higher incidence of liver steatosis (p = 0.016) or chronic ethanol abuse (p = 0.04). In comparison with the subgroup of favorable outcome, the patients with poor outcome were older, had higher values for ALT, bilirubin, lactate, and lower values for factor V and arterial pH. In multivariate analysis, the arterial lactate value was associated with a bad prognosis (p &lt, 0.02) (adjusted odds ratio 1.74 and CI 95:1.09&ndash, 2.77). The risk of poor outcome was greater in the subgroup with staggered overdose (p = 0.02), which had a higher mortality rate (p = 0.01). This retrospective analysis illustrates the different population patterns of patients who were admitted for a single ingestion of a paracetamol overdose versus multiple ingestions. This last subgroup was mainly represented by older patients with additional risk factors for hepatotoxicity, arterial lactate was a good predictor of severity.

showing Kaplan–Meier curves for 1-year mortality after discharge from the ICU, Figure S2. showing plots of restricted cubic spline of continuous variables included in the multivariable model, Figure S3. showing plots of restricted cubic spline of continuous variables included in the multivariable model, Table S1. presenting details on comorbidities and chronic treatment, and Table S2. presenting ORs (with 95% CI) for variables significantly associated with 1-year mortality in univariate analysis and in multivariable analysis (DOCX 110 kb)

Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability ( Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.

Hepatorenal syndrome (HRS) is a unique form of acute kidney injury seen in cirrhotic patients and associated with significant mortality and morbidity. Despite its impact, diagnosis and treatment of HRS remains challenging and this review aims to assess and compare the available vasoconstrictors used as first-line treatment for HRS. Areas covered: A literature review was undertaken on the use of vasoconstrictors in HRS, using PubMed/Medline database searches of: 'hepatorenal syndrome', 'HRS' and 'vasoconstrictor'. Expert commentary: Current diagnosis criteria are based on an exclusion-based approach using serum creatinine as a biomarker. However, this method relies on the measurement over a sustained period of time resulting in delayed treatment. Using urine biomarkers, the revised acute kidney injury guidelines and novel plasma expanders may improve diagnosis and the implementation of time-sensitive management of HRS. Vasoconstrictors are the first-line treatment for HRS, in which terlipressin is the vasoconstrictor of choice supported by current guidelines and a substantial clinical evidence base over other vasoconstrictors, such as noradrenaline or midodrine plus octreotide. Future developments in dosage and administrative techniques for terlipressin may have an important role to play in maintaining clinical efficacy whilst improving tolerability in the management of HRS.

Resume Les infections intra-abdominales sont une des urgences digestives les plus frequentes et une des premieres causes de choc septique. Une Conference de consensus sur la prise en charge des peritonites communautaires a ete publiee en 2000. Une reactualisation etait devenue indispensable tout comme l’edition de nouvelles recommandations pour des situations moins frequentes telles que les peritonites en pediatrie et celles associees aux soins. Les objectifs de cette Recommandation formalisee d’experts (RFE) ont donc ete de preciser la prise en charge medicale et chirurgicale des infections intra-abdominales communautaires, de definir les particularites en pediatrie et de decrire la prise en charge des infections associees aux soins. L’analyse de la litterature a ete declinee selon six grands themes : la demarche diagnostique, le controle de la source infectieuse, les informations microbiologiques, les particularites pediatriques, le traitement medical des peritonites, et la prise en charge des complications. La methodologie GRADE ® a ete appliquee pour determiner le niveau de preuve et la force de recommandation. Apres synthese du travail des experts et application de la methode GRADE ® , 62 recommandations ont ete formalisees par le comite d’organisation. Les recommandations ont ete soumises et amendees par un groupe de relecture. Apres 2 tours de cotations type Delphi et divers amendements, un accord fort a ete obtenu pour 44 (100 %) recommandations. Les RFE sur les peritonites ont permis d’obtenir un consensus entre les differentes specialites impliquees dans la prise en charge de ces patients sur un certain nombre de themes, tels que : (i) la strategie diagnostique et la place de l’iconographie ; (ii) le delai de prise en charge ; (iii) la place des prelevements microbiologiques ; (iv) les cibles des traitements anti-infectieux probabilistes ; (v) la duree du traitement anti-infectieux. Les RFE ont egalement permis de preciser l’interet et la place de certaines pratiques comme : (i) la place de la cœlioscopie ; (ii) les indications du drainage radiologique ; (iii) les indications du traitement des enterocoques et des levures. Les RFE ont egalement permis de confirmer l’inutilite de certaines pratiques comme : (i) l’usage diagnostique des biomarqueurs ; (ii) les relaparotomies systematiques ; (iii) les traitements anti-infectieux prolonges, particulierement en pediatrie.

Objectives: The growing incidence of infections caused by Enterobacteriaceae producing ESBLs has led to increased use of carbapenems. Temocillin, which resists most beta-lactamases, may be a useful alternative. The aim of this study was to assess the pharmacokinetics and target attainment rates of 6 g of temocillin daily divided into three administrations every 8 h (three times daily) or administered by continuous infusion in critically ill patients. Patients and methods: This was a prospective, two-centre, randomized, controlled study in patients with intra-abdominal or lower respiratory tract infections caused by Enterobacteriaceae. Results: Thirty-two patients were included and analysed for clinical efficacy, and pharmacokinetics were measured in 29 of them. Four patients undergoing continuous veno-venous haemofiltration (CVVH) were analysed separately. Mean, median and range of percentages of the dosing interval during which the free drug concentration remained >16 mg/L were 76.4, 98 and 18.7-98.9 in patients treated three times daily and 98.9, 89.7 and 36.4-99.9 in patients with continuous infusion, respectively. Clinical cure rates were 79% and 93% in each of these groups, respectively (not significant). Patients with CVVH received a daily dose of 750 mg given by continuous infusion and had a mean free drug concentration of only 13.8 +/- 1.9 mg/L. No adverse event attributable to temocillin was observed. Conclusions: Temocillin (6 g daily) given by continuous infusion allows a larger proportion of critically ill patients to have free drug serum concentrations covering infections caused by Enterobacteriaceae with an MIC of 16 mg/L compared with administration three times daily. Clinical efficacy compared with carbapenems in documented severe infections needs to be further studied.

High-flow nasal cannula use is developing in ICUs. The aim of this study was to compare aerosol efficiency by using two nebulizers through a high-flow nasal cannula: the most commonly used jet nebulizer (JN) and a more efficient vibrating-mesh nebulizer (VN).Aerosol delivery of diethylenetriaminepentaacetic acid labeled with technetium-99m (4 mCi/4 mL) to the lungs by using a VN (Aerogen SoloLung deposition was only 3.6 (2.1-4.4) and 1 (0.7-2)% of the nominal dose with the VN and the JN, respectively (p 0.05). The JN showed higher retained doses than the VN. However, both nebulizers were associated with substantial deposition in the single limb circuit, the humidification chamber, and the nasal cannula [58.2 (51.6-61.6)% of the nominal dose with the VN versus 19.2 (15.8-22.9)% of the nominal dose with the JN, p 0.05] and in the upper respiratory tract [17.6 (13.4-27.9)% of the nominal dose with the VN and 8.6 (6.0-11.0)% of the nominal dose with the JN, p 0.05], especially in the nasal cavity.In the specific conditions of the study, pulmonary drug delivery through the high-flow nasal cannula is about 1%-4% of the initial amount of drugs placed in the nebulizer, despite the higher efficiency of the VN as compared with the JN.

Background: Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. Methods: This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. Results: A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. Conclusions: In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation. Trial registration: ClinicalTrials.gov, NCT01000649. Registered on September 30, 2009., SCOPUS: ar.j, info:eu-repo/semantics/published

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

INTRODUCTION: The pharmacokinetic/pharmacodynamic index determining β-lactam activity is the percentage of the dosing interval (%T) during which their free serum concentration remains above a critical threshold over the minimum inhibitory concentration (MIC). Regrettably, neither the value of %T nor that of the threshold are clearly defined for critically-ill patients. Areas covered: We review and assess the targets proposed for β-lactams in critical illness by screening the literature since 1997. Depending on the study intention (clinical cure vs. suppression of resistance), targets proposed range from 20%T>1xMIC to 100%T>5xMIC. Assessment and comparative analysis of their respective clinical efficacy suggest that a value of 100%T>4xMIC may be needed. Simulation studies, however, show that this target will not be reached at first dose for the majority of critically-ill patients if using the most commonly recommended doses. Expert Commentary: Considering that critically-ill patients are highly vulnerable and likely to experience antibiotic underexposure, and because effective initial treatment is a key determinant of clinical outcome, we support the use of a target of 100%T>4xMIC, which could not only maximize efficacy but also minimize emergence of resistance. Clinical and microbiological studies are needed to test for the feasibility and effectiveness of reaching such a demanding target.

Background Acute pancreatitis (AP) is associated with high morbidity and mortality in its most severe forms. Most patients with severe AP require intubation and invasive mechanical ventilation, frequently for more than 7 days, which is associated with the worst outcome. Recent increasing evidence from preclinical and clinical studies support the beneficial effects of epidural analgesia (EA) in AP, such as increased gut barrier function and splanchnic, pancreatic and renal perfusion, decreased liver damage and inflammatory response, and reduced mortality. Because recent studies suggest that EA might be a safe procedure in the critically ill, we sought to determine whether EA reduced AP-associated respiratory failure and other major clinical outcomes in patients with AP. Methods and analysis The Epidural Analgesia for Pancreatitis (EPIPAN) trial is an investigator-initiated, prospective, multicentre, randomised controlled two-arm trial with assessor-blinded outcome assessment. The EPIPAN trial will randomise 148 patients with AP requiring admission to an intensive care unit (ICU) to receive EA (with patient-controlled epidural administration of ropivacaine and sufentanil) combined with standard care based on current recommendations on the treatment of AP (interventional group), or standard care alone (reference group). The primary outcome is the number of ventilator-free days at day 30. Secondary outcomes include main complications of AP (eg, organ failure and mortality, among others), levels of biological markers of systemic inflammation, epithelial lung injury, renal failure, and healthcare-associated costs. Ethics and dissemination The study was approved by the appropriate ethics committee ( CPP Sud-Est VI ). Informed consent is required. If the combined application of EA and standard care proves superior to standard care alone in patients with AP in the ICU, the use of EA may become standard practice in experienced centres, thereby decreasing potential complications related to AP and its burden in critically ill patients. The results will be disseminated in a peer-reviewed journal. Trial registration number NCT02126332.

Kidney-transplanted patients need adequate care in order to improve the kidney injury encountered during the surgical procedure related ischemia-reperfusion injury. In addition to avoiding nephrotoxic substances, the physician should be aware of the guidelines that recommend how to take care of these patients. Those guidelines include adequate fluid therapy to maintain a euvolemic status, which might be assessed by central venous pressure monitoring. There are no particular medications that may be proposed at the present time. Specific work-up with ultrasound or scintigraphic techniques might help in case of delayed graft function.

The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18–19, 2015. The main purpose of this meeting is to gather the best experts in the field in order to provide the highest quality update on a chosen topic. In 2015, the selected theme was: “Acute Renal Failure in the ICU: from injury to recovery.” The conference program covered multiple aspects of renal failure, including epidemiology, diagnosis, treatment and kidney support system, prognosis and recovery together with acute renal failure in specific settings. The present report provides a summary of every presentation including the key message and references and is structured in eight sections: (a) diagnosis and evaluation, (b) old and new diagnosis tools, (c) old and new treatments, (d) renal replacement therapy and management, (e) acute renal failure witness of other conditions, (f) prognosis and recovery, (g) extracorporeal epuration beyond the kidney, (h) the use of biomarkers in clinical practice http://www.srlf.org/5th-paris-international-conference-jeudi-18-et-vendredi-19-juin-2015/ .

The purpose of the study is to explore health care professionals' (HCPs) perceptions regarding sedation recommendations.This is a qualitative study, using face-to-face semistructured interviews. Health care professionals from 4 Belgian hospitals were purposively sampled. We focused on recommendations involving strategies such as protocolized sedation, sedation scales, daily sedation interruption (DSI), and providing analgesia before sedation. Knowledge, perceived barriers, expected outcomes, and responsibilities were discussed for each recommendation. Two researchers independently performed content analysis, classifying quotes according to an interdisciplinary framework and creating new categories for emerging themes.Data saturation was reached after 21 HCPs (physicians, nurses, and physiotherapists) were interviewed. Quotes were related to HCPs, guidelines or the system. Barriers were diverse according to the type of HCP or level of experience. Task characteristics impairing implementation of protocolized sedation included lack of means communicating goals or tasks to all HCPs providing care, ambiguous responsibilities, and unclear methodology on how to execute the recommendation. Fear of adverse events and lack of clarity regarding contraindications impair implementation of DSI.Barriers impairing implementation of sedation recommendations vary according to the type of HCP and the choice of strategy targeting light sedation (protocolized sedation vs DSI). Improvement strategies must target HCPs separately and tailored to specific recommendation choices.

Background Patients with lower airway Staphylococcus aureus (SA) colonization are at great risk (> 20%) of early-onset ventilator-associated pneumonia (VAP). Thus, a rapid test is required to identify patients at risk. Suvratoxumab (formerly MEDI4893) is a human monoclonal antibody that neutralizes SA alpha toxin. SAATELLITE, a phase 2 study of safety and efficacy of suvratoxumab for reducing the incidence of SA pneumonia (NCT02296320) was conducted and recently completed within the consortium for Combatting Bacterial Resistance in Europe. We investigated the performance of a rapid PCR test (Xpert MRSA/SA SSTI™, Cepheid) as a screening tool during the study and the association between SA load and suvratoxumab efficacy. Methods The PCR assay was used to detect SA and methicillin-resistant SA (MRSA) in lower respiratory tract (LRT) samples. Culture was performed on PCR SA+ LRT samples according to local procedures. PCR SA+ subjects were randomized 1:1 to either a single intravenous infusion of 5000 mg suvratoxumab (n = 96) or placebo (n = 100) and followed for 190 days post dose. Efficacy of suvratoxumab was defined as relative risk reduction (RRR) in incidence of SA pneumonia within 30 days post-dose compared with placebo. Results 299 (41.5%) out of 720 screened subjects were SA+ by PCR. Of 209 subjects with culture data, there were 162 (77.5%) SA+, 47 (22.5%) SA- and 9 (5.6%) MRSA by culture. Culture results could have been affected by antibiotic use and site variability in limits of detection ranging from 3.3 to 100,000 colony-forming units per mL (CFU/mL). No discordance was noted between PCR and culture for MRSA detection. An inverse linear correlation was observed between the PCR cycle threshold (Ct) values for SA protein A gene (spa) and SA CFU/mL counts from quantitative culture. In subjects with low SA load (Ct ≥ 29; n = 72), suvratoxumab provided 66.7% RRR [90% confidence interval (CI): 21.3%, 86.2%] compared with 31.9% RRR [90% CI: -7.5%, 56.8%] in total study population. Conclusion Cepheid Xpert PCR assay was easy to perform, sensitive and standardized, and provided better sensitivity than conventional culture for detection of SA. Additionally, quantitative PCR Ct output was associated with the efficacy of suvratoxumab in reducing SA pneumonia incidence. Disclosures All authors: No reported disclosures.

Background Staphylococcus aureus (SA) pneumonia imposes significant morbidity and mortality in mechanically ventilated, intensive care unit (MV ICU) patients despite best clinical care. We assessed efficacy, PK, AT-neutralizing antibodies (AT NAbs), and safety of suvratoxumab (suvra) in MV ICU subjects in the placebo-controlled, randomized Phase 2 SAATELLITE study (NCT02296320; EudraCT 2014-001097-34). Methods Subjects with PCR-confirmed SA colonization of the lower respiratory tract were randomized to either a single intravenous infusion of 5,000 mg suvra (n = 96) or placebo (n = 100) and followed for 190 days post dose. Efficacy endpoints were Endpoint Adjudication Committee-determined relative risk reduction (RRR) of SA pneumonia incidence in suvra vs. placebo recipients within 30 days post dose (primary endpoint, tested at 2-sided α = 0.1), incidence of all-cause pneumonia, and all-cause pneumonia or death. Serum suvra PK and levels of AT NAbs were measured through 90 days post dose and analyzed for statistical correlation. Treatment-emergent adverse events (TEAEs) and serious AEs (SAEs) were assessed through 190 days post dose. Results Baseline characteristics were similar between groups. Suvra provided 31.9% RRR in incidence of SA pneumonia vs. placebo (17.7% vs. 26%; P = 0.166), 30% RRR (P = 0.146) in incidence of all-cause pneumonia, and 23% RRR (P = 0.164) in incidence of all-cause pneumonia or death. Suvra reduced mean hospital stay and ICU duration by 3.0 and 2.4 days, resp. vs. placebo. Mean serum ± SD suvra level was 296 ± 131 µg/mL at 30 days post dose. Serum AT Nab ± SD levels reached 156.03 ± 72.48 IU/mL at 2 days post dose, declining slowly to 33.74 ± 16.04 IU/mL by 90 days post dose. AT NAbs correlated with PK (r2 = 0.7), thereby confirming functional activity of suvra over time. Proportion of subjects with TEAEs or SAEs was similar between groups: ≥1 TEAE (93.8% suvra; 93.0% placebo); ≥1 serious; and/or ≥grade 3 severity SAE (66.7% suvra; 58.0% placebo). Conclusion A single intravenous dose of suvra produced a trend toward reduced incidence of SA pneumonia, health resource savings, sustained functional exposure in serum, and an acceptable safety profile. These results support continued development of suvra in MV ICU patients. Disclosures All Authors: No reported Disclosures.

Background Critical care is a complex field of medicine, especially because of its diversity and unpredictability. Mortality rates of the diseases are usually high and patients are critically ill, admitted in emergency, and often have several overlapping diseases. This makes research in critical care also complex because of patients’ conditions and because of the numerous ethical and regulatory requirements and increasing global competition. Many clinical trials in critical care have thus failed and almost no drug has yet been developed to treat intensive care unit (ICU) patients. Learning from the failures, clinical trials must now be optimized. Main body Several aspects can be improved, beginning with the design of studies that should take into account patients’ diversity in the ICU. At the site level, selection should reflect more accurately the potential of recruitment. Management of all players that can be involved in the research at a site level should be a priority. Moreover, training should be offered to all staff members, including the youngest. National and international networks are also part of the future as they create a collective synergy potentially improving the efficacy of sites. Finally, computerization is another area that must be further developed with the appropriate tools. Conclusion Clinical research in the ICU is thus a discipline in its own right that still requires tailored approaches. Changes have to be initiated by the investigators themselves as they know all the specificities of the field.

The Innovative Medicines Initiative-funded COMBACTE consortium fosters academic-industry partnership in pioneering studies to combat serious bacterial infections. We describe how this partnership is advancing the development of 2 monoclonal antibodies, MEDI4893 and MEDI3902, for the prevention of nosocomial pneumonia.

Purpose The purpose of the study is to identify predictors of underuse of sedation scales and daily sedation interruption (DSI). Methods We surveyed all physicians and seven nurses in every Belgian intensive care unit (ICU), addressing practices and perceptions on guideline recommendations. Underuse was defined for sedation scales as use less than 3× per day and for DSI as never using it. Classification trees and logistic regressions identified predictors of underuse. Results Underuse of sedation scales and DSI was found for 16.6% and 32.5% of clinicians, respectively. Strongest predictors of underuse of sedation scales were agreeing that using them daily takes much time and being a physician (rather than a nurse). Further predictors were confidence in their ability to measure sedation levels without using scales, for physicians, and nurse/ICU bed ratios less than 1.98, for nurses. The strongest predictor of underuse of DSI among physicians was the perception that DSI impairs patients' comfort. Among nurses, lack of familiarity with DSI, region, and agreeing DSI should only be performed upon medical orders best predicted underuse. Conclusions Workload considerations hamper utilization of sedation scales. Poor familiarity, for nurses, and negative perception of impact on patients' comfort, for physicians, both reduce DSI utilization. Targeting these obstacles is essential while designing quality improvement strategies to minimize sedative use.

Additional file 1. Physiological responses during first transfer out of bed. Values expressed as mean ± standard deviation; * different from baseline, ≈ different from 5 min.

Shortening the turn-around time (TAT) of positive blood culture (BC) identification (ID) and susceptibility results is essential to optimize antimicrobial treatment in patients with sepsis. We aimed to evaluate the impact on antimicrobial prescription of a modified workflow of positive BCs providing ID and partial susceptibility results for Enterobacteriaceae (EB), Pseudomonas aeruginosa and Staphylococcus aureus on the day of BC positivity detection. This study was divided into a pre-intervention period (P0) with a standard BC workflow followed by 2 intervention periods (P1, P2) with an identical modified workflow. ID was performed with MALDI-TOF MS from blood, on early or on overnight subcultures. According to ID results, rapid phenotypic assays were realized to detect third generation cephalosporin resistant EB/P. aeruginosa or methicillin resistant S. aureus. Results were transmitted to the antimicrobial stewardship team for patient's treatment revision. Times to ID, to susceptibility results and to optimal antimicrobial treatment (OAT) were compared across the three study periods. Overall, 134, 112 and 154 positive BC episodes in P0, P1 and P2 respectively were included in the analysis. Mean time to ID (28.3 hours in P0) was reduced by 65.3% in P1 (10.2 hours) and 61.8% in P2 (10.8 hours). Mean time to complete susceptibility results was reduced by 27.5% in P1 and 27% in P2, with results obtained after 32.4 and 32.6 hours compared to 44.7 hours in P0. Rapid tests allowed partial susceptibility results to be obtained after a mean time of 11.8 hours in P1 and 11.7 hours in P2. Mean time to OAT was decreased to 21.6 hours in P1 and to 17.9 hours in P2 compared to 36.1 hours in P0. Reducing TAT of positive BC with MALDI-TOF MS ID and rapid susceptibility testing accelerated prescription of targeted antimicrobial treatment thereby potentially improving the patients' clinical outcome.