Join Section

Sepsis – 3, a New Definition. Solutions or New Problems?

Todd L. Slesinger, MD, FACEP, FCCM, FCCP, FAAEM
Laurence Dubensky, MD


Before we can discuss the “Sepsis-3” definitions, we need to look back at the history of Sepsis definitions, and what the rationale was leading the authors to create a new definition. Below is a brief, albeit non-exhaustive, timeline that visually represents the essentials of sepsis research and innovation over the past few decades. As you can see illustrated above, there has been an enormous, multi-specialty, multi-national approach to the understanding of sepsis care. Sepsis has been and remains a major cause of mortality and morbidity as well as a significant use of health care spending, costing more than $20 billion in the US alone. The severity of the disease is compounded by an increasing incidence. The reasons for this may be due to an aging population with increasing comorbidities, increased recognition and possibly due to changes in coding practices.
Sepsis-3
Although there has been extensive research, significant advances in the care of septic patients, and a great improvement in our understanding of what sepsis is and the underlying pathophysiology, we still have not achieved a thorough understanding or an accurate, subjective “tissue” diagnosis or definition. Before this definition, SIRS criteria, with which I'm sure we are all aware, was the mainstay for both screening at prognostication of patients with sepsis. That leads us to “Sepsis – 3”: The Third International Consensus Definitions for Sepsis and Septic Shock, which was presented at the 45th annual SCCM Critical Care Congress in Orlando on February 22, 2016. This was published as a trio of papers in JAMA the same day, as two were needed to explain the derivation and validation of these definitions.

As the authors state, this update was needed for many reasons, these include the fact that SIRS is non-specific (Kaukonen et al. NEJM 2015), there is now a much improved understanding of pathobiology, and most felt that SIRS is an expected inflammatory response to infection and other physiologic insults (burns, pancreatitis, etc.) As an aside, we need to also consider anti-inflammatory, hormonal, metabolic, coagulation, bio-energetic, neuronal and autonomic factors. Lastly, they felt that the existing terminology to describe sepsis could be confusing e.g. Severe Sepsis vs. Sepsis (septicemia, sepsis syndrome).

The 19-member Task Force who derived and validated the new definitions was comprised of intensivists, infectious disease specialists, surgeons and pulmonologists. They agreed to these key concepts and the following definitions:

Key Concepts:   

  • Sepsis is the primary cause of death from infection
  • Dysregulated host response
  • Organ dysfunction may be occult
  • Phenotypes may be modified by comorbidities / interventions
  • Infections may cause local dysfunction without a dysregulated response


Definition: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

To add some clarity about dysfunction, this is copied from the article:

Organ dysfunction can be identified as an acute change in total SOFA score ≥2 points consequent to the infection. The baseline SOFA score can be assumed to be zero in patients not known to have preexisting organ dysfunction. A SOFA score ≥2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with modest dysfunction can deteriorate further, emphasizing the seriousness of this condition and the need for prompt and appropriate intervention, if not already being instituted. (Of note, SOFA was described by JL Vincent in Intensive Care Medicine in 1996). 

Sepsis_2
They created a lay definition: In lay terms, sepsis is a life-threatening condition that arises when the body’s response to an infection injures its own tissues and organs.

qSOFA criteria:
 
Alteration in mental status (GCS < 14)
Hypotension - SBP ≤100 mm Hg
Respiratory rate ≥22/min.  


What caught a lot of attention was the development of a new term - qSOFA (or Quick SOFA). Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qSOFA.

Definition: Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.  
Please note: Severe sepsis was removed from the current definitions. 

Despite many endorsements from various societies (SCCM, American Thoracic Society, and the American Association of Critical Care Nurses), it has NOT been endorsed by ACEP, SAEM, ACCP, or IDSA due to extensive concerns. A primary concern for non-ICU providers is that these definitions have not been prospectively validated in a generalizable population, nor has it been validated or studied in the Emergency Department, pre-hospital or non-ICU, inpatient setting. Although the previous iterations of sepsis definitions, i.e., SIRS, sepsis, severe sepsis and shock, were by no means perfect as demonstrated by both scientific data and anecdotal experience, since their implementation massive improvements have been made in sepsis morbidity and mortality with a reduction from 40%-20%. Many critics state that SOFA and more specifically qSOFA will act equally insensitive to SIRS.
 
In non-ICU patients, SOFA and SIRS perform identically in predicting mortality (with an area under the curve of 0.79; 95% CI, 0.78-0.80 vs. 0.76; 95% CI, 0.75-0.77 and sensitivities of 68% and 64% respectively). This data suggests that in the Emergency Department, continuing to use SIRS, which has been widely adopted and in part has contributed to significant reductions in mortality as stated above, performs at the same level as the newly proposed, multi-stage, more complex and intensive replacement.
 
Additionally, qSOFA was derived to be a predictor of mortality and not a diagnostic or immediate prognostic screening tool, which as we have seen with ProCESS, ARiSe and ProMISE, early recognition and treatment are key to improved survival in sepsis. This is highly problematic in the ED or non-ICU setting as it can lead to delayed diagnosis and initiation of treatment. Narrowing the criteria will reduce sensitivity possibly leading to a higher risk of delayed diagnosis, which is more serious in low and middle income countries. Critics say high sensitivity is preferred over specificity because this is such a lethal syndrome. 
 
Changing the definition now when we are finally getting some traction, especially in non-academic institutions, could set back decades of work and could be interpreted to de-emphasize intervention at earlier stages when the syndrome is most treatable. Also, realistic adoption in the US with SEP-1 (CMS measure – see last month’s QIPS newsletter), is unlikely as the original definitions are used here for data abstraction, and there is no current plan to change those. Also coding and billing are based on ICD-10-CM Principal or other Diagnosis code of Sepsis, Severe Sepsis, or Septic Shock which is again based on current definitions.
 
So what’s going to happen? I believe that despite the use of social media, adoption will be very slow mainly because of the government-based processes. Prospective studies will be performed for validation especially on qSOFA. Future research will be tricky in comparing patients with different definitions of sepsis, as we saw with ARDS, which was not even a large paradigm shift. Time will tell.
 
  1. Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801 – 810. 
  2. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med.1992;20:864-874. 
  3. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med. 2003;29:530-538. 
  4. Nguyen H, Rivers E, Abrahamian F, et al. Emergency department sepsis education program and strategies to improve survival (ED-SEPSIS) working group. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. 2006;48(1):28-54. (Review)
  5. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546-1554.  
  6. Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35(8):1928-1936.  
  7. Levy MM, Dellinger RP, Townsend SR, et al, The Surviving Sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38(2):367-374.  
  8. Nguyen H, Rivers E, Abrahamian F, et al. Emergency department sepsis education program and strategies to improve survival (ED-SEPSIS) working group. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. 2006;48(1):28-54. 
  9. Nguyen H, Rivers E, Knoblich B, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004;32(8):1637-1642.  
  10. Rivers EP, Coba V, Whitmill M. Early goal-directed therapy in severe sepsis and septic shock: a contemporary review of the literature. Curr Opin Anaesthesiol. 2008;21(2):128-140.  
  11. Annane D, Bellissant E, Bollaert PE, et al, Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301(22):2362-2375. 
  12. Dhainaut J, Laterre P, Janes J, et al. Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intens Care Med. 2003;29(6):894-903. 
  13. Nadel S, Goldstein B, Williams M, et al. Researching severe sepsis and organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multi-centre phase III randomized controlled trial. Lancet. 2007;369(9564):836-843.  
  14. FDA Clinical Review. US Food and Drug Administration. Drotrecogin alfa (activated) [recombinant human activated protein C (rhAPC)] XigrisTM. 2001.  
  15. Jones AE, Shapiro NI, Trzeciak S, et al. (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739-746.  
  16. Rivers E, Nguyen B, Havstad S, et al. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.  
  17. Sprung CL, Annane D, Keh D, et al. CORTICUS Study Group. Hydrocortisone Therapy in Septic Shock.  N Engl J Med. 2008 Jan 10;358(2):111-24. 
  18. Lilly CM.  The ProCESS Trial — A New Era of Sepsis Management.  N Engl J Med 2014; 370:1750-1751. 
  19. The ARISE Investigators and the ANZICS Clinical Trials Group.  Goal-Directed Resuscitation for Patients with Early Septic Shock. N Engl J Med 2014; 371:1496-1506. 
  20. Mouncey PR, Osborn TM, et al.  Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med 2015; 372:1301-1311. 
  21. Holst LB, Haase N, Wetterslev J,et al. TRISS: Transfusion Requirements in Septic Shock. N Engl J Med 2014; 371(15):1381-91. 
  22. Russell JA, Walley KR, Singer J, et al. Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock. N Engl J Med 2008; 358:877-887. 
 
  
 
Feedback
Click here to
send us feedback