BACKGROUND-Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.

PURPOSE To investigate the association of endothelial-related markers with organ dysfunction and in-hospital mortality to validate our earlier findings in a multicenter study. We hypothesize that: 1) endothelial biomarkers will be associated with organ dysfunction and mortality in sepsis; and, that sFlt-1, holds promise as novel prognostic markers in sepsis. METHODS A prospective, multicenter, observational study of a convenience sample of Emergency Department (ED) patients with a suspected infection presenting to one of four urban, academic medical center EDs between January 2009 and January 2010. We collected plasma while the patients were in the ED, and subsequently assayed endothelial-related biomarkers, namely sFlt-1, sE-Selectin, sICAM-1, sVCAM-1, and PAI-1. Outcomes were organ dysfunction and in-hospital mortality. RESULTS We enrolled at a total of 166 patients: 63 with sepsis (38%), 61 with severe sepsis (37%) and 42 with septic shock (25%). All endothelial biomarkers were significantly associated with sepsis severity, P < 0.002. We found a significant inter-correlation between all biomarkers, strongest between sFlt1 and PAI-1 (r=0.61, P < 0.001) and PAI-1 and sE-selectin and sICAM-1 (r=0.49, P < 0.001). Among the endothelial biomarkers, sFlt-1 had the strongest association with SOFA score (r=0.58, P < 0.001). sFlt-1 and PAI-1 had the highest area under the operating receiver characteristic curve for mortality of 0.87. CONCLUSIONS This multi-center validation study confirms that markers of endothelial activation are associated with sepsis severity, organ dysfunction and mortality in sepsis. This supports the hypothesis that the endothelium plays a central role in the pathophysiology of sepsis and may serve as a more accurate prediction tool and a target for therapies aimed at ameliorating endothelial cell dysfunction. Additionally, sFLT-1 holds promise as a novel sepsis severity biomarker.

The early, accurate diagnosis and risk stratification of sepsis remains an important challenge in the critically ill. Since traditional biomarker strategies have not yielded a gold standard marker for sepsis, focus is shifting towards novel strategies that improve assessment capabilities. The combination of technological advancements and information generated through the human genome project positions systems biology at the forefront of biomarker discovery. While previously available, developments in the technologies focusing on DNA, gene expression, gene regulatory mechanisms, protein and metabolite discovery have made these tools more feasible to implement and less costly, and they have taken on an enhanced capacity such that they are ripe for utilization as tools to advance our knowledge and clinical research. Medicine is in a genome-level era that can leverage the assessment of thousands of molecular signals beyond simply measuring selected circulating proteins. Genomics is the study of the entire complement of genetic material of an individual. Epigenetics is the regulation of gene activity by reversible modifications of the DNA. Transcriptomics is the quantification of the relative levels of messenger RNA for a large number of genes in specific cells or tissues to measure differences in the expression levels of different genes, and the utilization of patterns of differential gene expression to characterize different biological states of a tissue. Proteomics is the large-scale study of proteins. Metabolomics is the study of the small molecule profiles that are the terminal downstream products of the genome and consists of the total complement of all low-molecular-weight molecules that cellular processes leave behind. Taken together, these individual fields of study may be linked during a systems biology approach. There remains a valuable opportunity to deploy these technologies further in human research. The techniques described in this paper not only have the potential to increase the spectrum of diagnostic and prognostic biomarkers in sepsis, but they may also enable the discovery of new disease pathways. This may in turn lead us to improved therapeutic targets. The objective of this paper is to provide an overview and basic framework for clinicians and clinical researchers to better understand the 'omics technologies' to enhance further use of these valuable tools.

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Objectives: Microcirculatory dysfunction plays an important role in sepsis pathophysiology. Previous studies using sidestream dark-field (SDF) imaging have demonstrated microcirculatory flow abnormalities in patients with septic shock; however, the microcirculation is relatively unstudied in lower-acuity sepsis patients. The hypothesis was that patients with sepsis, but without hypotension, will demonstrate signs of flow abnormalities compared to noninfected control patients.Methods: This was a prospective, observational study in a convenience sample of patients with sepsis and noninfected controls, conducted in three urban, tertiary care emergency departments (EDs) in the United States. Sepsis was defined as suspected infection plus two or more systemic inflammatory response syndrome (SIRS) criteria; those with hypotension were excluded. Noninfected controls were ED patients without infection and without SIRS criteria. SDF imaging was obtained in all study patients during ED evaluation. Recommended microcirculatory flow parameters were measured, and the difference in these measures between sepsis patients and noninfected controls were calculated. The authors also correlated microcirculatory flow parameters with patient variables, including serum lactate.Results: A total of 106 patients were enrolled: 63 with sepsis and 43 noninfected controls. There were no differences in microcirculatory flow scores between sepsis patients and noninfected controls. Median microvascular flow index (MFI; with interquartile range [IQR] was 3.00 (IQR = 2.73 to 3.00) in sepsis patients versus 2.93 (IQR = 2.73 to 3.00) in control patients (p = 0.33), and mean proportion of perfused small vessels (PPV) was 91.5% (95% CI = 89.7% to 93.3%) versus 91.8% (95% CI = 89.7% to 93.9%), with a mean difference of 0.3% (95% CI = -2.5% to 3.1%; p = 0.84). Similarly, there were no significant differences in total vessel density, perfused vessel density, or heterogeneity index (HI). In the subset of infected patients for whom serum lactates were obtained (n % 37), MFI and PPV were negatively correlated with elevated serum lactate values: r = -0.32, p = 0.04; and r = -0.44, p < 0.01, respectively.Conclusions: Measureable microcirculatory flow abnormalities were not observed in patients with early sepsis in the absence of hypotension. However, microcirculatory abnormalities were correlated with elevated serum lactate in normotensive sepsis patients, supporting the notion that impaired microcirculatory flow is coupled with cellular distress.ACADEMIC EMERGENCY MEDICINE 2014; 21:154-162

The clinical decision rule performed well in our ED setting and is likely to be a useful supplement to clinical judgment.

The number of organ dysfunctions predicts sepsis mortality.