1. SEPSIS 3:THE CHANGES, CONCERNS AND FACTS

3. OUTLINE Why the need of a definition? The changes The concerns
Definitions over the years
The concerns
What would I do in my practice?

4. LOUIS PASTEUR •
Isolated bacteria from patient with puerperal sepsis
“Natura medicatrix won the victory”

5. 100YEARS LATER…AND OVER 100000 ARTICLES…
ne of the oldest and most elusive syndromes in
medicine”

6. HOW COMMON IS THE SYNDROME?
Sepsis
most common reasons for admission to ICUs throughout the world.
SOAP II trial
Septic shock 62 %
Cardiogenic shock 17 % and hypovolemia (16 %)
De Backer D, et al. "Comparison of dopamine and norepinephrine in the treatment of shock". The New England
Journal of Medicine (9):

7. SEPSIS RUN…

8. IMPACT OF SEPSIS Extended hospital and ICU stay High mortality
Death from septic shock were often in excess of 80% as recently as 30 years ago.
Mortality ranges from 20% (US data) to 65% (Indian data*)
Epidemiology of severe sepsis in India: an update S Todi et al Crit Care. 2010; 14(Suppl 1): P382.

9. THE DEMAND FOR A DEFINITION…
Clinician Patient Trialist
Epidemiologist
Trigger specific treatments
Discard alternate diagnosis
Inform patients
Prefer discrete diagnosis
Whom to enroll in a study
Track incidence and outcome

10. BARCELONA DECLARATION
Action demanded on the world’s oldest killer
Estimated that 1400 people die from sepsis each day
Brought together 3 leading professional organizations
ESICM, SCCM and the International sepsis forum
Debut of the Surviving sepsis campaign
Aimed to decrease the mortality of sepsis by 25% over 5 years

11. SEPSIS-DEFINING A DISEASE CONTI UUM..

12. WHAT’S THE PROBLEM WITH MAKING A DEFINITION FOR SEPSIS?
No gold standard for diagnosis
Can’t calculate sensitivity and specificity
Don’t know the true positives and negative
How do you measure validity in the absence of a gold standard?
Predictive validity
Prediction of events that we can measure and that are common after sepsis
Face validity

13. Good screening tool-high sensitivity
GOOD DEFINITION
Good screening tool-high sensitivity
Pick up early
High specificity
Face validity
Utility
Good definition
Predictive validity
Objective

14. EVOLUTION OF THE DEFINITION OF SEPSIS

15. PRE 1980
Sepsis
Included all patients even with septic shock

16. 1980-1991 Suspected or Documented infection +
SEPSIS
Suspected or Documented infection +
Temp>38°C or <36°C
HR>90/min
RR> 20/min
With evidence of at least 1 organ dysfunction:
Altered mental status
Hypoxemia
Elevated lactate
Oliguria>1 hour
SEPTIC SHOCK
Systolic BP <90 mmHg or a reduction of ≥40 mmHg from baseline in the absence of other causes of hypotension

17. 1991 ACCP SCCM CONSENSUS DEFINITION
Better understanding of the pathophysiology
Bring in the systemic inflammatory response syndrome to infection
Laid down broad definitions
Early bedside detection
Early interventions with better outcomes

18. SEPSIS: DEFINING A DISEASE CONTINUUM
Infection/ Trauma
SIRS
Sepsis
Severe Sepsis
Bone et al. Chest. 1992;101:1644.

19. INFECTION: PART OF A BIGGER PICTURE
Presence of organisms in a closed space or location where not normally found
Infection
rom: Bone RC et al. Chest. 1992;101: t al. Crit Care Med. 2000;28:S81-2.

20. SIRS: SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
A clinical response arising from a nonspecific insult manifested by
2 of the following:
Temperature
38°C or 36°C
HR 90 beats/min
RR20/min
WBC count 12,000/mL or
4,000/mL or >10% immature neutrophils
pted from: Bone RC et al. Chest. 1992;101: l SM et al. Crit Care Med. 2000;28:S81-2.

21. SEPSIS: MORE THAN JUST INFLAMMATION
Known or suspected infection
SIRS criteria
pted from: Bone RC et al. Chest. 1992;101:

22. SEVERE SEPSIS: ACUTE ORGAN DYSFUNCTION
Sepsis with signs of acute organ dysfunction in any of the following systems:
Cardiovascular
Renal
Respiratory
Hepatic
Hemostasis
CNS
Unexplained metabolic acidosis
Adapted from: Bone RC et al. Chest. 1992;101:

23. SEPTIC SHOCK
Arterial hypotension despite “adequate” fluid resuscitation.
Systolic BP <90 mmHg or a reduction of ≥40 mmHg from baseline in the absence of other causes of hypotension

24. 2001 CONSENSUS DEFINITION
ACCP, SCCM, ESICM, ATS, SIS

25. OBJECTIVES Review strengths and weaknesses of 1991 definition
Identify methods to improve accuracy of the definition

26. THE MAIN CHANGE 2001…
Focused on developing definition that would facilitate a clinical diagnosis at the bedside over research
Expanded the SIRS concept
Possible signs of systemic inflammation in response to Infection

27. SEPSIS=INFECTION +”SOME” OF THE FOLLOWING

28. No change in severe sepsis or septic shock definitions
2001 CONSENSUS DEFINITION
PIRO Staging system for Sepsis
No change in severe sepsis or septic shock definitions

29. OVER THEYEARS…

30. 24YEARS LATER  2000-2013 Over 1 million patients in ANZIC ICUs
To detect if this was really a good screening tool for sepsis
N Engl J Med 2015;372:

31. SENSITIVITY ANaD SPECIFICITY FACE VALIDITY
Lacks sensitivity for defining sepsis (at least
• 1 in 8 ICU patients with infection and org criteria
Not specific
n patients admitted to ICU)
n dysfunction do not have 2 or more SIRS i
SENSITIVITY ANaD SPECIFICITY FACE VALIDITY
PREDICITIVE VALIDITY
4 in 5 ICU patients without infection have ‘SIRS’ criteria Poor face validity and criterion validity

32. PROBLEMS WITH PREVIOUS DEFINITIONS
‘Septic shock’ requires refractory hypotension to be present
However hypotensive patients do not necessarily have shock
AND
Patients in shock may not be hypotensive

33. 1991 AND 2001- WERE THEY GOOD DEFINITIONS?

35. SEPSIS 3

36. AGENDA OF THE TASK FORCE
Differentiate sepsis from uncomplicated infection
AND
Update definitions of sepsis and septic shock to be consistent with improved understanding of the pathobiology

37. WHAT’S DIFFERENT? Did away with SIRS and “Severe sepsis”
Only 2 definitions
Sepsis
Septic shock

38. IN ORDER TO INCREASE FACE VALIDITY
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection
Clinical criteria
Suspected or documented infection and an acute increase of ≥2 SOFA points (a proxy for organ dysfunction)
Organ dysfunction when infection is first suspected is associated with an in- hospital mortality in excess of 10%.(more than mortality for STEMI)

39. SEPTIC SHOCK
Septic shock is a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality
Clinical criteria: Sepsis AND
Vasopressor therapy needed to elevate MAP ≥65 mm Hg AND
Lactate >2 mmol/L despite adequate fluid resuscitation
Both criteria met = 40% mortality

40. SEPSIS CONTINUUM…
pted from: Bone RC et al. Chest. 1992;101: l SM et al. Crit Care Med. 2000;28:S81-2.

41. SEPSIS CONTINUUM..
Sepsis
Uncomplicated Infection
Septic shock

43. Q SOFA AS A SCREENING TOOL FOR MORTALITY PREDICTION
>2 of the following criteria
Hypotension
Systolic BP<100mmHg
Altered mentation-GCS<13
Tachypnea-RR>22/min

44. PROPOSED ALGORITHM

45. L SEPSIS 3 HAS MADE HISTORY!!
One of the most highly accessed articles in recent years
Viewed more than one million times on the JAMA website
Flurry thoug
st all
of commentaries–some supportiv
e, some opposing, and almo
htful…

46. OME OF THE PROBLEMS WIT SEPS S 3…
CONCERNS..

47. POINT 1: CONTINUES TO REMAIN SUBJECTIV
“Suspected infection” in all 3 Sepsis definitions
Little discussion to determine how to do so..
May not really help in picking up sepsis early

48. POINT 2: UTILITY
Q SOFA
Easy
SOFA
Not easy to remember

49. SOFA…

50. POINT 3: WILL WE BE TOO LATE?
Older definitions
Do not require organ failure to be present
May capture patients earlier before organ failure takes place
New algorithm
Does not encourage early diagnosis
False re-assurance

51. POINT 3: WILL WE BE TOO LATE??

53. POINT 4: SPECIFICITY
Mortality predictors and NOT tests to detect sepsis
Positive qSOFA Sepsis
Must not miss other diagnosis!

54. Q SOFA MAY BE LESS SPECIFIC IN DISEASES THAT AFFECT THE HEART, LUNG OR BRAIN

55. LOW SPECIFICITY
MAY OVER-ADMIT PATIENTS IN ICU…RESOURCE LIMITED SETTINGS

56. POINT 5: IS Q SOFA A GOOD “SCREENING” TOOL?
Pulmonary embolism
Screening tool – D dimer
Sensitivity very high-therefore false negatives very low
Confirmatory test- CTPA
High specificity-therefore false positives very low
What about in sepsis?

57. IN ORDER TO PREDICT MORTALITY
Inside ICU
Criteria
Area under ROC curve
Sensitivity
Specificity
SIRS>2 Criteria
0.64
64%
65%
SOFA>2
0.74
68%
67%
qSOFA >2
0.66
55%
84%
Assessment of Clinical Criteria for Sepsis
For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Seymour et al
JAMA. 2016;315(8):

58. GOING BACK TO THE ALGORITHM

59. Q SOFA AS A SCREENING TEST AND SOFA AS A DEFINITIVE TEST??
On face value this makes sense, because qSOFA is a simple and fast, whereas the full SOFA test is labor intensive.
However, the specificity of SOFA is actu lly lower than the specificity of qSOFA, making this test sequence illogical.
Thus, SOFA adds little to qSOFA among patients outside the ICU

60. RECENT PUBLICATION…

61. POINT 6: PREDICTIVE VALIDITY
Mortality outside ICU
AUROC
Q SOFA -0.81
 SOFA-0.79
 SIRS-0.76
Mortality inside ICU
SIRS 0.64
qSOFA
0.66
SOFA 0.74
Assessment of Clinical Criteria for Sepsis
For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) S
JAMA. 2016;315(8):

62. POINT 7: UTILITY IN ALL PARTS OF THE WORLD?
Low and middle income regions
Focus is on early recognition and treatment of sepsis
Patients with isolated hypotension or a reduced level of consciousness will be classified as “uncomplicated infection”
No representation from any of these regions or emergency medicine
Have not endorsed this new definition

63. 2016 SEPSIS DEFINTION

64. THE STORY CONTINUES…
A satisfactory clinical definition of sepsis continues to elude us since the ancient Greeks first coined the term.

65. Re-defining syndromes creates exciting headlines, but it is unclear if
improves patient care.

66. TO SUM UP SEPSIS 3 Does it make sense??
Re-defining a syndrome which is heterogeneous and trying to put it under one umbrella
For a disease which is common and with a high mortality
Still a subjective definition
Little guidance regarding what exactly is meant by “suspected infection.”
May capture patients late once organ dysfunction has happened
qSOFA and SOFA are predictors of mortality, they are not tests for sepsis.
qSOFA probably as good or as bad as SIRS
May over treat in a resource limited setting

67. UNTIL PROSPECTIVE VALIDATION …
If q SOFA positive
Consider infection as an underlying cause
Simultaneously rule out other causes of organ dysfunction
Investigate and monitor for further organ dysfunction, and

68. WHAT WOULD I DO?
The SIRS and sepsis definitions do not require organ failure to be present
May capture patients earlier
May prompt rapid initiation of life-saving interventions.
Moreover, these previous definitions and the SIRS criteria have been widely adopted for in various clinical trials
Decreasing mortality trend over the past 25 years
Does not make sense to discard them until there is unquivocal evidence that Sepsis 3 is superior.

69. WHAT WOULD I DO?
" I can't define obscenity, but I know it w en I see it.” United States Supreme Court Justice Potter Stewart, 1964
Until a compelling argument is made
Will continue encouraging the use of the old definitions combined with clinical judgment

70. THANK YOU