Sepsis definitions: time for change.

For the Ancient Greeks, sepsis referred to rot, decay, or putrefaction. Galen and Celsus described the signs of infl ammation as peripheral vasodilatation (rubor), fever (calor), pain (dolor), increased capillary permeability (tumor), and organ dysfunction (functio laesa). The modern concept of sepsis has focused on the human response to invading organisms. In 1991, a North American consensus conference introduced the idea that sepsis is the host’s infl ammatory response to in fection. For simplicity, the systemic infl ammatory re sponse syndrome (SIRS) was defi ned by four variables: temperature, heart rate, respiratory rate, and white blood cell count. Only minor abnormalities in these variables are needed for a patient to meet the SIRS criteria. These simple clinical criteria allowed researchers to identify patients to enrol in sepsis trials and were rapidly adopted. However, the SIRS approach has three major problems. First, the SIRS criteria are so sensitive that up to 90% of patients admitted to an intensive care unit (ICU) meet the criteria. SIRS can be caused by many non-infectious clinical processes, such as severe trauma, burns, pancreatitis, and ischaemic reperfusion events. If sepsis is defi ned by the presence of SIRS criteria plus an infection, and almost every acutely ill patient meets the SIRS criteria, then sepsis eff ectively equals infection. But, although all patients with sepsis have an infection, the reverse is not necessarily true—ie, not all patients with an infection have sepsis. Second, some degree of host response is actually inherent to the infection; indeed, this is an important component of the diff erence between infection and mere colonisation. Almost any infection—even a minor viral illness—is typically asso ciated with fever and accompanying changes, including tachycardia, some hyperventilation, and an increased white cell count. This host response has benefi cial aspects, and a reduced or absent reaction could suggest that the individual is immunocompromised. Third, deciphering the role of infection in the pathogenesis of SIRS has been diffi cult because sterile infl ammation (present in, for example, severe trauma, burns, and pancreatitis) and infection can both elicit similar clinical signs of acute systemic infl ammation. Moreover, several such stressors might be present simultaneously in any patient. A second consensus conference in 2001 attempted to revisit the SIRS criteria but failed to come up with an easyto-use list of variables to defi ne sepsis. By expanding the list of potential clinical criteria, the delegates risked making the defi nition less specifi c. The delegates attempted to list major and minor criteria, as for endocarditis, but could not identify any meaningful criteria. Hence, the 1991 criteria for sepsis continue to be used. To reach a more precise defi nition of sepsis than the SIRS criteria provide, we need to establish whether sepsis is the same as sterile infl ammation. Several noninfectious processes that are associated with acute tissue injury and innate immune activation can induce a clinical syndrome analogous to sepsis (fi gure), including multiple trauma, pancreatitis, transplant rejection, and autoimmune diseases. Whether this syndrome is mediated by endogenous endotoxin or by non-infectious stimuli can be very diffi cult to defi ne. However, we know that sepsis arises through activation of an innate immune response to a stimulus that represents a danger to the host. From a molecular perspective, the initial host response to infection does not diff er appreciably from the host response to sterile infl am mation from severe trauma, burns, ischaemic reper fusion injury, or other forms of tissue injury that are accompanied by cell necrosis. Work over the past few decades has shown that pattern recognition receptors, such as those of the Toll-like receptor (TLR) and the nucleotide-binding oligo merisation domain (NOD) protein families, initiate the distinct cellular responses. Together these responses produce the phenotypic changes of sepsis. The receptors are activated by conserved mi crobial molecular structures, such as endotoxin or lipoteichoic acid. But the pattern recognition receptors used by the innate immune system to engage microbial ligands are the same receptors that recognise alarmins derived by host tissue and that are pathologically present in the extracellular environment. For example, high mobility group box 1 (HMGB1) is released during sterile injury and signals through TLR4 to mediate organ damage, even in the absence of infection. Both invasive infection and sterile tissue necrosis thus cause immediate activation of infl ammatory, coagulation, microbial clearance, and tissue repair pathways to stabilise and defend the host from further injury. Clinical signs alone fail to distinguish this sterile infl ammatory Lancet 2013; 381: 774–75