Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Surviving sepsis: going beyond the guidelines

The Surviving Sepsis Campaign is a global effort to improve the care of patients with severe sepsis and septic shock. The first Surviving Sepsis Campaign Guidelines were published in 2004 with an updated version published in 2008. These guidelines have been endorsed by many professional organizations throughout the world and come regarded as the standard of care for the management of patients with severe sepsis. Unfortunately, most of the recommendations of these guidelines are not evidence-based. Furthermore, the major components of the 6-hour bundle are based on a single-center study whose validity has been recently under increasing scrutiny. This paper reviews the validity of the Surviving Sepsis Campaign 6-hour bundle and provides a more evidence-based approach to the initial resuscitation of patients with severe sepsis

Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort

Objectives:We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.Methods: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.Results: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT(> MIC) (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving beta-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P=0.012]. Additionally, in patients with a SOFA score of >= 9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P=0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P=0.025].Conclusions: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: “AbSeS”, a multinational observational cohort study and ESICM Trials Group Project

Purpose: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion: This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection

Are CT-Based Finite Element Model Predictions of Femoral Bone Strengthening Clinically Useful?

Purpose of Review: This study reviews the available literature to compare the accuracy of areal bone mineral density derived from dual X-ray absorptiometry (DXA-aBMD) and of subject-specific finite element models derived from quantitative computed tomography (QCT-SSFE) in predicting bone strength measured experimentally on cadaver bones, as well as their clinical accuracy both in terms of discrimination and prediction. Based on this information, some basic cost-effectiveness calculations are performed to explore the use of QCT-SSFE instead of DXA-aBMD in (a) clinical studies with femoral strength as endpoint, (b) predictor of the risk of hip fracture in low bone mass patients. Recent Findings: Recent improvements involving the use of smooth-boundary meshes, better anatomical referencing for proximal-only scans, multiple side-fall directions, and refined boundary conditions increase the predictive accuracy of QCT-SSFE. Summary: If these improvements are adopted, QCT-SSFE is always preferable over DXA-aBMD in clinical studies with femoral strength as the endpoint, while it is not yet cost-effective as a hip fracture risk predictor, although pathways that combine both QCT-SSFE and DXA-aBMD are promising

Non-invasive prediction of the mouse tibia mechanical properties from microCT images: comparison between different finite element models

New treatments for bone diseases require testing in animal models before clinical translation, and the mouse tibia is among the most common models. In vivo micro-Computed Tomography (microCT)-based micro-Finite Element (microFE) models can be used for predicting the bone strength non-invasively, after proper validation against experimental data. Different modelling techniques can be used to estimate the bone properties, and the accuracy associated with each is unclear. The aim of this study was to evaluate the ability of different microCT-based microFE models to predict the mechanical properties of the mouse tibia under compressive load. Twenty tibiae were microCT scanned at 10.4 µm voxel size and subsequently compressed at 0.03 mm/s until failure. Stiffness and failure load were measured from the load–displacement curves. Different microFE models were generated from each microCT image, with hexahedral or tetrahedral mesh, and homogeneous or heterogeneous material properties. Prediction accuracy was comparable among models. The best correlations between experimental and predicted mechanical properties, as well as lower errors, were obtained for hexahedral models with homogeneous material properties. Experimental stiffness and predicted stiffness were reasonably well correlated (R2 = 0.53–0.65, average error of 13–17%). A lower correlation was found for failure load (R2 = 0.21–0.48, average error of 9–15%). Experimental and predicted mechanical properties normalized by the total bone mass were strongly correlated (R2 = 0.75–0.80 for stiffness, R2 = 0.55–0.81 for failure load). In conclusion, hexahedral models with homogeneous material properties based on in vivo microCT images were shown to best predict the mechanical properties of the mouse tibia