Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1288-3) contains supplementary material, which is available to authorized users.

We compared the ultrastructure and synaptic targets of terminals of cortical or retinal origin in the stratum griseum superficiale and stratum opticum of the rat superior colliculus. Following injections of biotinylated dextran amine into cortical area 17, corticotectal axons were labeled by anterograde transport. Corticotectal axons were of relatively small caliber with infrequent small varicosities. At the ultrastructural level, corticotectal terminals were observed to be small profiles (0.44 Ϯ 0.27 m 2 ) that contained densely packed round vesicles. In tissue stained for gamma amino butyric acid (GABA) using postembedding immunocytochemical techniques, corticotectal terminals were found to contact small (0.51 Ϯ 0.69 m 2 ) non-GABAergic dendrites and spines (93%) and a few small GABAergic dendrites (7%). In the same tissue, retinotectal terminals, identified by their distinctive pale mitochondria, were observed to be larger than corticotectal terminals (3.34 Ϯ 1.79 m 2 ). In comparison to corticotectal terminals, retinotectal terminals contacted larger (1.59 Ϯ 1.70 m 2 ) nonGABAergic dendrites and spines (73%) and a larger proportion of GABAergic profiles (27%) of relatively large size (2.17 Ϯ 1.49 m 2 ), most of which were vesicle-filled (71%). Our results suggest that cortical and retinal terminals target different dendritic compartments within the neuropil of the superficial layers of the superior colliculus. Anat Rec Part A, 288A: 850 -858, 2006.

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