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Sepsis continues to be a devastating, costly, and challenging syndrome to manage in emergency departments (ED) across the nation, and its impact seems to be only increasing. Recently, consensus recommendations have made some profound changes in the way we approach, classify, and treat sepsis. The ED serves as an important initial screening and intervention point for sepsis, and ED care can have a profound impact on overall morbidity and mortality. The provision of early fluid resuscitation, antimicrobial therapy, and vasopressor therapy, if appropriate, is essential in early care. The intent of this review was to compare and contrast changes associated with the management of sepsis in the ED, with particular focus on guideline recommendations for pharmacotherapeutic management.