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PurposeThe 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).MethodsThe 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).Results364 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.ConclusionElevated 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.

Extracorporeal membrane oxygenation (ECMO) is a mode of extracorporeal life support that augments oxygenation, ventilation and/or cardiac output via cannulae connected to a circuit that pumps blood through an oxygenator and back into the patient. ECMO has been used for decades to support cardiopulmonary disease refractory to conventional therapy. While not robust, there are promising data for the use of ECMO in acute hypoxemic respiratory failure, cardiac arrest, and cardiogenic shock and the potential indications for ECMO continue to increase. This review discusses the existing literature on the potential use of ECMO in critically ill patients within the emergency department.

Abstract Rationale We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. Objectives We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. Methods We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. Measurements and Main Results Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)2/1,000 was 92% (95% confidence interval [CI], 85–98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06–0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4–22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63–0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80–0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). Conclusions Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)2/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Changes in receptor signaling, excessive production of nitric oxide, and absolute or relative deficiencies of vasoactive hormones, including cortisol, vasopressin, and angiotensin II, play a role. Interest was re-ignited following the Angiotensin II for the Treatment of Vasodilatory Shock (ATHOS-3) study, a randomized controlled trial in patients with refractory shock which confirmed that Ang II was effective at maintaining mean arterial pressure and reducing norepinephrine requirements without an increase in side effects [1]. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury.

Background Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. Methods We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60–0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. Results In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. Conclusions Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive. Graphical abstract

Evaluate the impact of an emergency critical care center (EC3) on the admissions of critically ill patients to a critical care medicine unit (CCMU) and their outcomes. This was a retrospective before/after cohort study in a tertiary university teaching hospital. To improve the care of critically ill patients in the emergency department (ED), a 9-bed EC3 was opened in the ED in February 2015. All critically ill patients in the emergency department must receive intensive support in EC3 before being considered for admission to the CCMU for further treatment. Patients from the emergency department account for a significant proportion of the patients admitted to the CCMU. The proportions of patients admitted to the CCMU from the ED were analyzed 1 year before and 1 year after the opening of the EC3. We also compared the admission data, demographic data, APACHE III scores and patient outcomes among patients admitted from ED to the CCMU in the year before and the year after the opening of the EC3. The establishment of the EC3 was associated with a decreased proportion of patients admitted to the CCMU from the ED (OR 0.73 95% CI 0.63–0.84, p < 0.01), a decrease in the proportion of patients with sepsis admitted from the ED (OR 0.68, 95% CI, 0.54–0.87, p < 0.01) and a decrease in the proportion of patients with gastrointestinal bleeding admitted from the ED (OR 0.49, 95% CI 0.28–0.84, p < 0.05). Following the establishment of the EC3, patients admitted to the CCMU had a higher APACHE III score in 2015 (74.85 ± 30.42 vs 72.39 ± 29.64, p = 0.015). Fewer low-risk patients were admitted to the CCMU for monitoring following the opening of the EC3 (112 [6.8%] vs. 181 [9.3%], p < 0.01). Propensity score matching analysis showed that the opening of the EC3 was associated with improved 60-day survival (HR 0.84, 95% CI 0.70–0.99, p = 0.046). Following the opening of the EC3, the proportion of CCMU admissions from the ED decreased. The EC3 may be most effective at reducing the admission of lower-acuity patients with GI bleeding and possibly sepsis. The EC3 may be associated with improved survival in ED patients. •The opening of Emergency Critical Care Center may decrease the admissions from the emergency department.•The opening of Emergency Critical Care Center may be most effective in avoiding admission in lower acuity patients with GI bleed or sepsis.•The opening of Emergency Critical Care Center may be associated with improved survival of patients from ER.

Increased patient acuity, decreased intensive care unit (ICU) bed availability, and a shortage of intensivist physicians have led to strained ICU capacity. The resulting increase in emergency department (ED) boarding time for patients requiring ICU-level care has been associated with worse outcomes. To determine the association of a novel ED-based ICU, the Emergency Critical Care Center (EC3), with 30-day mortality and inpatient ICU admission. This retrospective cohort study used electronic health records of all ED visits between September 1, 2012, and July 31, 2017, with a documented clinician encounter at a large academic medical center in the United States with approximately 75 000 adult ED visits per year. The pre-EC3 cohort included ED patients from September 2, 2012, to February 15, 2015, when the EC3 opened, and the post-EC3 cohort included ED patients from February 16, 2015, to July 31, 2017. Data analyses were conducted from March 2, 2018, to May 28, 2019. Implementation of EC3, an ED-based ICU designed to provide rapid initiation of ICU-level care in the ED setting and seamless transition to inpatient ICUs. The main outcomes were 30-day mortality among ED patients and rate of ED to ICU admission. A total of 349 310 visits from a consecutive sample of ED patients (mean [SD] age, 48.5 [19.7] years; 189 709 [54.3%] women) were examined; the pre-EC3 cohort included 168 877 visits and the post-EC3 cohort included 180 433 visits. Implementation of EC3 was associated with a statistically significant reduction in risk-adjusted 30-day mortality among all ED patients (pre-EC3, 2.13%; post-EC3, 1.83%; adjusted odds ratio, 0.85; 95% CI, 0.80-0.90; number needed to treat, 333 patient encounters; 95% CI, 256-476). The risk-adjusted rate of ED admission to ICU decreased with implementation of EC3 (pre-EC3, 3.2%; post-EC3, 2.7%; adjusted odds ratio, 0.80; 95% CI, 0.76-0.83; number needed to treat, 179 patient encounters; 95% CI, 149-217). Implementation of a novel ED-based ICU was associated with improved 30-day survival and reduced inpatient ICU admission. Additional research is warranted to further explore the value of this novel care delivery model in various health care systems.

Studies of acute myocardial infarction, trauma, and stroke have been translated into improved outcomes by earlier diagnosis and application of therapy at the most proximal stage of hospital presentation. Most therapies for these diseases are instituted prior to admission to an ICU; this approach to the sepsis patient has been lacking. In response, a trial comparing early goal-directed therapy (EGDT) vs standard care was performed using specific criteria for the early identification of high-risk sepsis patients, verified definitions, and a consensus-derived protocol to reverse the hemodynamic perturbations of hypovolemia, vasoregulation, myocardial suppression, and increased metabolic demands. Five years after the EGDT publication, there has been much discussion generated with regard to the concepts of EGDT, as well as debate fueled regarding diagnostic and therapeutic interventions. However, during this time period further investigations by the primary investigators and others have brought additional contemporary findings. EGDT modulates some of the components of inflammation, as reflected by improved organ function. The end points used in the EGDT protocol, the outcome results, and the cost-effectiveness have subsequently been externally validated, revealing similar or even better findings than those from the original trial. Although EGDT is faced with challenges, a coordinated approach to sepsis management is necessary to duplicate the progress in outcomes seen in patients with conditions such as acute myocardial infarction, stroke, and trauma.