Changing Definition of Sepsis- New Inroads

Dr Neisevilie Nisa

All India Institute of Medical Sciences

Why sepsis again..?• Its magnitude on public health

• $20 billion of total US hospital cost 2011 (Torio et al)

• $2000 crore = Rs 1,33,944 crores

• 3.97 % of GDP 2013 = Rs 33,150 crore

• AIIMS budget = Rs 1,340 crore (2013-14)

The need to upgrade definitions…

“To know what distinguishes sepsis from an

uncomplicated infection”

“…. We need to differentiate a straight forward

infection from one that can cause organ

dysfunction or death…….”

Old definition and its limitation

1991 consensus conference (Sepsis-1)

• Introduced SIRS (Systemic Inflammatory

response syndrome)

• Sepsis complicated by organ dysfunction= severe

sepsis

• Septic shock= Sepsis induced hypotension

persistent despite adequate fluid resuscitation

2001 Task Force (Sepsis-2)

• Expanded the list of diagnostic criteria

• No other alternatives offered due to lack of

evidence

• Definitions have remained unchanged for more

than 2 decades

The validity of SIRS challenged…

• Are all infection sepsis…?

• Which kind of infection leads to sepsis…?

• Uncertain pathobiology

• No gold standard diagnostic test

• Poor Discriminant Validity

• Poor Concurrent Validity

• SIRS criteria have been used to diagnose sepsis for

more than 20 years.

• “SIRS no longer has any legs….. it sounded like a

good idea in 1992, but it has lost steam….”

Developing new definitions

• European Society of Intensive Care Medicine

• Society of Critical Care Medicine

“ Shift of focus from Inflamation to Organ

Dysfunction”

New definitions• Sepsis: A life-threatening organ dysfunction caused by a

dysregulated host response to infection.

• Septic shock: Sepsis in which underlying circulatory and

cellular/metabolic abnormalities are profound enough to

substantially increase mortality.

• Terms like severe sepsis/ septicemia removed

Criteria for new definitions

• SOFA score ≥ 2 points consequent to the infection.

• Baseline SOFA score is assumed to be zero

• SOFA score ≥ 2 overall mortality risk 10%

Evidence behind SOFA score

Two outcomes:

1) Hospital mortality

2) ICU stay of 3 days or longer

Consort diagram

ICU encounters (n=7932)

Non-ICU encounters (n=66522)

SOFA and LODS superior to SIRS with higher

Predictive Validity to represent organ dysfunction

Limitations of SOFA

• Cumbersome due to multiple variables

• Not well known outside ICU setting

• Variables and cutoff values were developed by

consensus

Quick SOFA( q SOFA) Seymor et al

Early Screening for Performance Improvement

Parameters Criteria

Respiratory rate ≥22/min

Altered mentation GCS <13

Systolic blood pressure ≤100mmHg

q SOFA ≥ 2 Predictive validity outside ICU setting = 81 %

Evidence of q SOFA• Poor man’s SOFA

• Quick and repeat bedside test

• No laboratory test required

– Outside ICU settings

– Emergency

– Wards

Predictive validity outside ICU setting = 81 %

Remarkable 3 vital signs model returning results with a

model that has multiple lab test (SOFA)

Changing definition of Septic Shock• First Consensus Definitions in 1991 and revisited

in 2001 Septic shock defined as a state of cardiovascular

dysfunction associated with infection and unexplained by

other causes

• No differentiation between Septic Shock and Cardiovascular Dysfunction

• To recognize the importance of Cellular Abnormalities

• Meta-analysis and systemic reviews from January 1, 1992- December 25,2015• 44 septic shock studies• 166,479 patients

Three variables identified

• Hypotension

• Elevated serum lactate level

• Sustained need for vasopressor therapy

Mortality significantly higher (p< .001) in patients with fluid resistant hypotension requiring vasopressors and hyperlactatemia (42.3 %)

‘VS’

Hyperlactatemia alone “or”

Fluid resistant hypotension requiring vasopressors

but Lactate level ≤ 2 mmol/L (30.1%)

Lactate > 2 mmol/L for predicting mortality in Septic Shock

Sensitivity = 82.5 %

Specificity = 22.4 %

New definition of Septic shock

• A clinical construct of sepsis with persisting

hypotension requiring vasopressors to maintain MAP

65mmHg and having a serum lactate level >2 mmol/L

(18mg/dL) despite adequate volume resuscitation

• With these criteria, hospital mortality is in excess of 40%

A subset of sepsis in which underlying circulatory and

cellular metabolism abnormalities are profound enough to

substantially increase mortality

How it differs from old definition..??

• Both serum lactate level and vasopressor-

dependent hypotension instead of either alone

• Lower serum lactate level cutoff of 2 mmol/L vs 4

mmol/L as currently used in the SSC definitions

• Fewer patients will be diagnosed, but a more robust

characterization

• More precise diagnosis

• Better epidemiological tracking

Summary

• Sepsis: A life-threatening organ dysfunction caused by a

dysregulated host response to infection.

• SOFA score ≥ 2 points = Organ Dysfunction

• SOFA score to evaluate sepsis in ICU settings

• q SOFA score to evaluate sepsis outside the ICU

• Septic shock: Sepsis in which underlying circulatory and

cellular/metabolic abnormalities are profound enough to

substantially increase mortality.

• Terms like severe sepsis/ septicemia removed

Operationalization of Clinical Criteria

Controversies and limitations• Most data extracted from US databases

• q SOFA and SOFA can miss occult organ dysfunction

• Specific infections can cause local organ dysfunction

without dysregulated systemic host response

• Non-availability of lactate measurements in resource

poor settings

• Task force focused on adult patients

Conclusion It took us more than 10 years to understand sepsis, now we

will have to change it all….

“…. Is it the final word in sepsis..?... Or the starting point of

discussion and additional research into this deadly

condition……”

Thank you

References • Torio CM, Andrews RM. National inpatient hospital costs: the most expensive conditions

by payer, 2011. Statistical Brief #160. Healthcare Cost and Utilization Project (HCUP) Statistical Briefs.August 2013.Accessed October 31, 2015

• Bone RC, Balk RA, Cerra FB, et al. 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(6):864-874.

• 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;29(4):530-538.• Seymour CW, Liu V, Iwashyna TJ, et al Assessment of clinical criteria for sepsis. JAMA. Doi:

10.1001/jama.2016.0288.• 13. Shankar-HariM, Phillips G, LevyML, et al Assessment of definition and clinical criteria

for septic shock. JAMA.doi:10.1001/jama.2016.0289• Singer M, Deutschman CS, Seymour CW, et al.The Third International Consensus

Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA.doi:10.1001/jama.2016.0287.