Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G₁ cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.

The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to stabilise macrocirculation and microcirculation to optimise the patient's tolerance to bleeding. Finally, targeted interventions should be used to reduce intraoperative and postoperative bleeding, and so prevent subsequent morbidity and mortality. The objective of these updated guidelines is to provide healthcare professionals with an overview of the most recent evidence to help ensure improved clinical management of patients. For this update, electronic databases were searched without language restrictions from 2011 or 2012 (depending on the search) until 2015. These searches produced 18 334 articles. All articles were assessed and the existing 2013 guidelines were revised to take account of new evidence. This update includes revisions to existing recommendations with respect to the wording, or changes in the grade of recommendation, and also the addition of new recommendations. The final draft guideline was posted on the European Society of Anaesthesiology website for four weeks for review. All comments were collated and the guidelines were amended as appropriate. This publication reflects the output of this work.

Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.)

Objectives: To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. Background: PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. Methods: A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). Results: Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55–0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference −0.43, 95% CI −0.54 to −0.31, P < 0.00001), hospital length of stay (mean difference −0.45, 95% CI −0.65 to −0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74–0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80–0.98, P = 0.02). Conclusions: Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta-analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.

Purpose The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI). Methods The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724). Results 364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75. Conclusion Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.