Sepsis-3: International Consensus Definitions for Sepsis and Septic Shock

REVIEW OF THE ARTICLES – What's new?

Despite the wide implementation of life support measures in ICU, sepsis remains the leading cause of death from infection. This syndrome, especially in the absence of early recognition and prompt treatment, may evolve into septic shock, which is a more severe illness with a much higher mortality rate. The clinical picture of sepsis, as a syndrome, is shaped by an entire cohort of physiopathological and biochemical abnormalities that occur during the complex interaction between pathogen virulence and host immune-inflammatory response [1]. An up-to-date definition of sepsis, with precise clinical characterisation, is of paramount importance to aid physicians in daily clinical practice and investigators in designing trials for new therapeutic approaches or in reporting epidemiological surveys.

The first definition of the septic syndrome established in 1992 was based on the concomitant presence of presumed/confirmed infection and at least two of four Systemic Inflammatory Response Syndrome (SIRS) criteria [2]. Although sensitive, this definition lacked specificity and it was later updated to include an expanded list of both clinical and laboratory abnormalities [3]. Up until now, the presence of organ dysfunction during sepsis has been identified as ‘Severe Sepsis’ and the occurrence of hypotension despite fluid resuscitation has characterised ‘Septic Shock’. However, in recent years, increased scientific knowledge of sepsis pathophysiology and the evidence of poor clinical and epidemiological utility of previous classifications has highlighted the need for new definitions and better characterisation of these terms. Hence, in 2014, the European Society of Intensive Care Medicine (ESICM) and the Society of Critical Care Medicine (SCCM) convened a Task Force of 19 critical care, infectious disease, surgical and pulmonary specialists with the aim to update the definitions and clinical criteria identifying the ‘septic patient’. The results of this international consensus has been just published in JAMA (Sepsis – 3) [4].

The current evidence regarding the ‘pathobiology’ of sepsis was discussed by the Task Force in iterative discussions, e-mail correspondence and voting. Discriminant and  convergent validity of existing clinical criteria and definitions for patients with suspected infections at risk of sepsis were reassessed in light of the availability of large electronic record databases and patient cohorts [5]. In addition, septic shock definition and clinical criteria were revaluated on the basis of a consensus process using a systematic review, surveys and cohort studies [6]. The new clinical criteria are also aimed at aiding practitioners in pre-hospital, emergency departments and hospital wards to promptly recognise and treat septic patients, i.e. those infected patients likely to fare badly. Importantly, the recommendations have been peer-reviewed and endorsed by major societies around the world.

KEY DEFINITIONS

• Sepsis is now defined as a ‘life-threatening organ dysfunction due to a dysregulated host response to infection’. In this new definition the concept of the non-homeostatic host response to infection is strongly stressed while the SIRS criteria have been removed. The SIRS criteria are considered overly non-specific and of poor clinical utility: i.e. they may be present in simple, non-complicated infection, or in response to non infectious-triggers (i.e. trauma, pancreatitis, post-cardiac arrest syndrome), or may even be absent in critically ill patients with obvious evidence of a life-threatening infection. While recognition and treatment of the infectious trigger obviously remain important, the attention with sepsis is now more focused on the pathobiology of the host response and the related organ dysfunction. The inflammatory response accompanying infection (pyrexia, neutrophilia, etc) often represent an appropriate host response to any infection, and this may not necessarily be life-threatening. 

• The key element of sepsis-induced organ dysfunction is defined by ‘an acute change in total SOFA score ≥ 2 points consequent to infection, reflecting an overall mortality rate of approximately 10%’. The baseline Sepsis-related Organ Failure Assessment (SOFA) score may be taken as zero unless the patient is known to have previous comorbidity (e.g. head injury, chronic kidney disease, etc). In light of this, the current definition of 'severe sepsis' becomes obsolete, as does the term. 

• Screening Tool: The qSOFA! The Sepsis-related Organ Failure Assessment (SOFA) score is widely used in the critical care setting and is a reliable tool to clinical characterise septic patients, but it requires some laboratory investigations and may be less useful for a quick screening patients in settings outside of the ICU. A simple bedside score (‘qSOFA’, for quick SOFA) has been proposed, which incorporates hypotension (systolic blood pressure ≤100mmHg), altered mental status and tachypnea (respiratory rate > 22/min): the presence of at least two of these criteria strongly predicts the likelihood of poor outcome in out-of-ICU patients with clinical suspicion of sepsis.

• Septic shock is now defined as a ‘subset of sepsis where underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality’. Clinical criteria identifying such condition include the need for vasopressors to obtain a MAP≥ 65mmHg and an increase in lactate concentration > 2 mmol/L, despite adequate fluid resuscitation. This new definition is mainly focused on the importance to both distinguish septic shock from other forms of circulatory shock and underline the detrimental clinical impact of sepsis-induced cellular metabolism abnormalities. 

• Given the urgent need to widely spread education campaigns and better inform the public about the clinical and economic implications of such condition, a lay definition of sepsis as ‘a life-threatening condition that arises when the body’s response to infection injures its own tissue’ has been also endorsed. Finally, all these new definitions are recommended for coding and research purposes. 

Despite the unavoidable limits affecting any definition of syndromes that do not have any specific diagnostic clinical, imaging, laboratory or biochemical marker, this new classification includes the most recent deep understanding of sepsis biology and stresses the clinical relevance of organ dysfunction. In addition, similarly to software updates, the Sepsis-3 definition has been established with the aim of fostering future updates.

Take Home Message

New definitions of sepsis and septic shock are now available. These rely on the importance of recognising when an adaptive and protective host response becomes maladaptive, impairing organ function. SIRS criteria may still guide clinicians toward identifying an ongoing infectious process, but ‘severe sepsis’ is no longer a part of the new classification. Hypotension and lactate level are key points underpinning the new septic shock criteria, as they reflect metabolic and cellular abnormalities characterising the pathobiology of sepsis. The Task Force conceived this definition as a transitional statement, which eliminates some of the issues related to previous classifications while, at the same time, advocating for more clear confirmation of the syndrome in daily clinical practice. The authors clearly note that this definition should and will be updated in the future, as our understanding of this complex syndrome continues to evolve. 

This article review was prepared by Gennaro De Pascale on behalf of the ESICM NEXT Committee.

References

1.    Shankar-Hari M, Deutschman CS, Singer M. Do we need a new definition of sepsis? Intensive Care Med. 2015 May;41(5):909-11.
2.    Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee.  American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55.
3.    Levy MM, Fink MP, Marshall JC, et al; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003 Apr;29(4):530-8.
4.    Singer M, Deutschman CS, Seymour CW, et al: The Sepsis Definitions Task Force The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). (JAMA, Feb 22, 2016). 
5.    Seymour CW, Liu V, Iwashyna TJ, et al. Assessment of clinical criteria for sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). (JAMA, Feb 22, 2016).
6.    Shankar-Hari M, Phillips G, Levy ML, et al. Assessment of definition and clinical criteria for septic shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). (JAMA, Feb 22, 2016).