Sepsis has been recognized in some form or another since at least 1,000 BC — when it was first described by the Islamist philosopher Ibn Sīnā (also known as Avicenna) as putrefaction of blood and tissues with fever1. Further described by Boerhaave, von Liebig, Semmelweis, Pasteur, Lister, Lennhartz and, most recently, Bone, sepsis and its treatment have confounded investigators for nearly 3,000 years. Since 1991, the consensus definition of sepsis has been the ‘systemic inflammatory response (SIRS) to a microbial infection’ (REFS 2,3) (BOX 1), with SIRS defined as at least two of the following: tachypnoea (rapid breathing), tachycardia (rapid heartbeat), pyrexia (fever) or hypothermia, and leukocytosis, leukopaenia or neutrophilia. Efforts have recently focused on eliminating the SIRS requirement entirely4 (BOX 2) because fever, tachycardia, tachypnoea and white blood cell changes reflect infection only and have proven to be too broadly applied in critically ill patients to be useful in the definition of sepsis. In its place, sepsis is now defined as an infection associated with organ injury distant from the site of infection. Septic shock remains defined as a subset of sepsis in which the risk of mortality is substantially increased, and is characterized by hypotension that persists during volume resuscitation and requires the use of vasopressors.
The study of sepsis treatment reflects progress in our understanding of human pathophysiology and host- microorganism interactions. Early research focused on the microorganism and its pathogenicity. In the 1980s, with the implementation of molecular cloning and the sequencing of human inflammatory genes, research in sepsis turned towards investigations that focused less on the pathogenicity of the microorganism and more on the host response to an invading pathogen5-7. The discovery of how the host distinguishes self and non-self and the introduction of the ‘danger hypothesis’ (REF.8) have dramatic ally improved our understanding of sepsis and its pathogenesis. The danger hypothesis purports that the innate immune system recognizes microbial patterns and unique host cellular products as ‘danger signals’ or ‘alarmins’ of microbial invasion or tissue injury. However, research has also revealed that the progression of sepsis is much more complex than just inflammation or microbial or host pattern recognition; sepsis also involves effects on endothelial tissues and microcirculation, primary and secondary immune tissues, coagulation, parenchymal tissues and neurological disturbances that directly affect microglial cells and neurons9-12.
Despite a dramatic increase in our understanding of sepsis, its origins, progression and resolution (recovery or death), our ability to intervene and alter the trajectory of the disease has been only partially successful. That is, our increased understanding of the pathogenesis of the disease has generally failed to substantially improve outcomes. Although in-hospital mortality from sepsis has declined over the past decade13, this improvement is more commonly attributed to earlier recognition and better compliance with best-practice supportive therapies14,15. In this Primer, we describe the contemporary definitions and the current epidemiological picture of sepsis and septic shock, as well as the best practices for the recognition and support of patients with sepsis and the use of potential biomarkers and biological response modifiers to better identify patients and treat them effectively.