Sepsis is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors. If left untreated, it may lead to the functional impairment of one or more vital organs or systems [4].There are many well-known risk factors for the infections that most commonly precipitate organ dysfunction, including acquired immunodeficiency syndrome, chronic obstructive pulmonary disease, many cancers, the use of immunosuppressive agents, and advanced age [5]. Although big steps forward have been made, the pathophysiological mechanisms for organ dysfunction are not entirely known, but it has become apparent that infection triggers a much more complex, variable, and prolonged host response, involving early activation of both pro- and anti-inflammatory responses.
Sepsis has variable clinical presentations depending on the initial site of infection, the causative organism, the pattern of acute organ dysfunction, and the underlying health status of the patient [5].
There is general consensus that early recognition and timely treatment largely determine outcome of sepsis.
Since the first classification in 1991 [1], the definition of sepsis, severe sepsis, and septic shock, though imprecise, have provided the clinicians a useful framework for clinical management, stressing the need for early recognition [6], and when these criteria are followed by the application of the Surviving Sepsis Campaign recommendations, they have an impressive history of success in reducing the mortality of sepsis in several areas of the world [7].
Several studies demonstrated that sepsis-related mortality reduced steadily over the years. A meta-analysis reported a reduction of sepsis 28-day mortality rates from 46.9% during the period 1991–1995 to 29% during 2006–2009 [8]. In the USA, mortality due to severe sepsis decreased by 51% from 1988 to 2012 [9]. In Australia and New Zealand, an overall decrease of 16.7% in hospital sepsis mortality was reported between 2000 and 2012 (from 35 to 18.4%) [10]. However, high mortality rates are still reported in low- and middle-income countries [11].
Despite decades of sepsis research, no specific therapies for sepsis have emerged. Without specific therapies, management is based on control of the infection and organ support.
Early antibiotics, source control, and fluid resuscitation support of vital organ function are the cornerstones for the treatment of patients with sepsis [12].
Timing and adequacy of source control are the most important issues in the management of patients with complicated intra-abdominal infections (cIAIs) because inadequate and late operation may have a negative effect on outcome. Source control was considered an essential element in the management of patients with complicated intra-abdominal infections (cIAIs) and should be considered and performed early after the diagnosis is established in most if not all patients [13]. Sotto et al. in 2002 found in a retrospective study that time between diagnosis and operation was associated with mortality [14]. In this study, the period between diagnosis and surgery was predictive of death within 30 days after diagnosis of peritonitis, emphasizing the importance of prompt surgical treatment. In the CIAOW (complicated intra-abdominal infections worldwide) observational study including 1898 consecutive patients older than 18 years undergoing surgery or interventional drainage to address IAI, a delayed initial intervention was found to be an independent variable predictive of mortality. In this study, the overall mortality rate was 10.5% (199/1898) [15].
To enable early interventions being effective, the diagnosis must be made as early as possible and treatment must be started early. The ability to identify septic patients who are at high risk for subsequent organ dysfunction and mortality, starting from pre-hospital care and ED, is crucial since timely recognition and appropriate, effective treatment substantially improves survival. This highlights the need for all healthcare workers to be vigilant about sepsis, so that the diagnosis can be made as early as possible [16].
One consequence of the new definitions is elimination of the concept of sepsis without organ dysfunction. Although the task force considered that the new definitions may better reflect the current understanding of sepsis pathophysiology, the literal interpretation of “sepsis” as a problem only when life-threatening organ dysfunction appears may be of limited utility in identifying patients who may benefit from early intervention.
The Sepsis-3 definitions requiring the presence of organ dysfunction to define sepsis may hinder the awareness of the importance of early recognition and treatment of infections before organ dysfunction appears, de-emphasizing intervention at earlier stages when it is most treatable.
Ideally, patients at risk for sepsis should be identified before organ dysfunction is established. Therefore, it may be questionable if it is helpful to have a definition that recognizes a patient once organ dysfunction has occurred and the patient already needs intensive care.
An observational study conducted at 132 medical institutions worldwide over a 4-month study period enrolled 4533 patients to validate a predictive score for patients with intra-abdominal infections [17]. Data from the WSES cIAIs Score Study (WISS) showed that mortality was significantly affected by the previous sepsis definition. Mortality with no sepsis was 1.2%, with sepsis only 4.4%, with severe sepsis 27.8%, and with septic shock was 67.8%. Severity of illness and the inherent mortality risk escalated from no sepsis, through sepsis, severe sepsis, and septic shock.
The previous stratification of the severity and consequent mortality due to infection that progressed from no sepsis to sepsis (infection meeting the criteria for systemic inflammatory response syndrome or SIRS), to severe sepsis (sepsis with organ failure, arterial hypertension, and/or hypoperfusion), to septic shock (arterial hypotension refractory to adequate volume resuscitation) is now reduced to simple infection, sepsis (infection and organ dysfunction), and septic shock (arterial hypotension defined as the use of vasopressors and hyperlactatemia). The previous concept of severe sepsis corresponds now to the definition of sepsis in the Sepsis-3 criteria, although this correlation is not absolute because sepsis, according to the new criteria, can include very different conditions, such as organ failure without hypotension nor hyperlactatemia [7].
The Sepsis-3 definitions exclude patients with isolated hypotension from the definition of sepsis because they would have a SOFA score of 1. Moreover, lactate is not part of the SOFA score, even though it is well documented to be a sensitive marker of severity of illness in patients with infection.
The Sepsis-3 definitions recommend using an increase in the SOFA score of 2 or more points to represent organ dysfunction. The SOFA score is intended to be used in the ICU and, to a lesser extent, the ED. Outside the ICU, SOFA was found only as good as the previous SIRS criteria (AUROC = 0.79 vs. AUROC = 0.76). Moreover, it is a valuable predictor of unfavorable outcome. The SOFA score was proposed in 1996 by the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine [18] to objectively describe the degree of organ dysfunction over time and to evaluate morbidity in patients in the ICU with sepsis. It was demonstrated to be a good indicator of prognosis in critically ill patients during the first few days of ICU admission [19]. The use of the SOFA score in research is commonly performed and constitutes a routine component of data collection for clinical trials in ICUs. However, the SOFA score is not universally accessible, especially for PaO2, which would require an arterial blood gas measurement.
Recognizing these practical limitations, the task force described a simplified method termed the “quick SOFA” (qSOFA) score to facilitate easier identification of patients potentially at risk of dying outside of critical care settings [20]. This instrument, which had not been validated in clinical practice at the time of Sepsis-3 publication, comprises three clinical parameters that are easy to assess outside the ICU.
The prognostic accuracy for in-hospital mortality of qSOFA is an area of great debate. A recent multicenter prospective cohort study involving 879 patients with suspected infection treated in the ED reported that qSOFA may be better than previous criteria at predicting in-hospital mortality among patients with suspected infection [21]. Nevertheless, we calculated the positive predictive value (PPV) of qSOFA for in-hospital death in this study to be only 0.24. This indicates that only one-quarter of the patients who had a qSOFA equal or more than 2 died in the hospital.
A recent large retrospective cohort analysis of 184,875 patients in 182 Australian and New Zealand intensive care units (ICUs) found that SOFA score had superiority in prediction of in-hospital mortality and that SIRS criteria had a greater prognostic accuracy for in-hospital mortality than qSOFA score [22].
In an observational cohort study performed at one ED at an urban university teaching hospital in Norway [23], qSOFA failed to identify two thirds of the patients admitted to an ED with severe sepsis. Further, qSOFA failed to be a risk stratification tool as the sensitivity to predict 7-day and 30-day mortality was low. The sensitivity was poorer than the other warning scores already in use at the study site and the SIRS criteria.
In a study of 886 patients, Tusgul et al. showed that the qSOFA score, SIRS criteria, and sepsis definition have low identification sensitivity in selecting septic patients in the pre-hospital setting or upon arrival in the ED [24].
An important limitation of the new definitions is the poor sensitivity of the qSOFA scoring system. This leads to a high number of false negatives and, subsequently, to a delayed diagnosis in many patients, which likely excludes its use as a screening tool for early sepsis, the stage in which treatment is most effective.
In a recent analysis of three prospectively collected, observational cohorts of 7754 infected emergency department patients aged 18 years or older, Henning et al. [25] demonstrated that the mortality rate for patients with a qSOFA score greater than or equal to 2 was 14.2%, with a sensitivity of 52% and specificity of 86% to predict mortality. In comparison, the original SIRS-based Sepsis-2 definition had a mortality rate of 6.8%, a sensitivity of 83%, and a specificity of 50%. Both the Sepsis-2 and Sepsis-3 definitions stratified patients at risk for mortality, with differing performances. In terms of mortality prediction, the new definitions had improved specificity but had very low sensitivity.
Williams et al. prospectively studied 8871 consecutive patients who were admitted from the ED with presumed infection and compared the diagnostic accuracy of SIRS with qSOFA and Sepsis-2 with Sepsis-3 definitions for organ dysfunction [26]. SIRS was associated with increased risk of organ dysfunction and mortality in patients without organ dysfunction. SIRS and qSOFA showed similar discrimination for organ dysfunction. qSOFA was specific but poorly sensitive for organ dysfunction. Mortality for patients with organ dysfunction was similar for Sepsis-2 and Sepsis-3, although 29% of patients with Sepsis-3 organ dysfunction did not meet Sepsis-2 criteria. Increasing numbers of Sepsis-2 organ system dysfunctions were associated with greater mortality.
In another study in which 3346 patients with infection outside the ICU and 1058 patients with infection in the ICU were analyzed, qSOFA provided inadequate sensitivity for early risk assessment [27].
Peake et al. performed a post hoc analysis of 1591 adult patients presenting to the ED with early septic shock [28]. At baseline, 1139 patients had a qSOFA score of ≥ 2. In contrast, 1347 participants met the Sepsis-3 criteria for sepsis. Of these, 1010 participants had a qSOFA score of ≥ 2 and met the Sepsis-3 criteria for sepsis. A quarter of participants who met the new sepsis definitions did not fulfill the qSOFA screening criteria, potentially limiting its utility as a screening tool for sepsis in the ED.
Sepsis requires urgent recognition because delayed treatment increases mortality. To optimize the timing of therapy, a screening test should be as sensitive as possible. Thus, it is preferable to have a more sensitive test with lower false negative results in order to not miss cases of serious sepsis.
Although some patients with ongoing sepsis may not have elevated lactate levels at presentation or during their clinical course [29], lactate measurement is advised as an important component of the initial evaluation of patients with sepsis. Elevated lactate levels (even if > 4 mmol/l) are no longer part of organ dysfunction criteria to define organ failure.
In the new definition of septic shock, hyperlactatemia is a required component for septic shock, differently from Sepsis-1 and Sepsis-2 definitions in which just the presence of refractory hypotension to fluid loading was considered shock. Therefore, when lactate measurements are not available, the diagnosis of septic shock can be more challenging and patients with potential shock will be considered as having only sepsis.