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Sepsis-3:clarity or confusion

Christopher W. Seymour, MD MScThe CRISMA CenterAssistant Professor of Critical Care Medicine & Emergency MedicineUniversity of Pittsburgh School of Medicine

Can an otherwise healthy 58-year-old man die from a bad cold? He

can, and he did. Through an unfortunate cascade of events, starting

with a missed diagnosis of viral pneumonia, Tom Wilson, a systems

analyst for Westinghouse, went from bad to worse until every major

organ system -- kidneys, liver, lungs and finally his heart -- stopped

working.

After 10 days in intensive care during which doctors struggled in vain to

get ahead of the rampaging disorder, Mr. Wilson died.

Cause of death: septic shock .

New York Times, March 5, 2002

• Minor illness• Healthy guy• Delay in the diagnosis of septic shock• Absence of specific tests• “Rampaging disorder” with organ dysfunction

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• Why is defining sepsis important?

• Why is defining sepsis difficult?

• Conceptual approach by the 2016 Sepsis Definitions Task Force

• Review of Sepsis-3

• Controversies post-release

Objectives

Sepsis is everywhere.

2

million US cases each year

5

percent of US healthcare spending

Gaieski et al. Crit Care Med, 2014Singer et al., JAMA, 2016

Liu et al., JAMA, 2014

Sepsis is everywhere.

1 out of every 2 to 3 hospital deaths

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We don’t talk about it.

Stroke

Heart attack

Sepsis

12%

10%

20%

Seymour et al., Am J Resp Crit Care Med, 2014

Why is defining sepsis difficult?

Angus et al., Crit Care Med, 2016

• Sepsis is common

• We don’t agree on the terms

• Surface phenomena lead to small zone of rarity with lots of patients

• Time-sensitive diagnosis

• Knowledge is rapidly evolving

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2016 Sepsis Definitions Task Force

• To re-examine existing criteria for sepsis and septic shock

• Does current pathophysiology, epidemiology mandate an

update?

• Use expert consensus to develop a definition• Use data to develop clinical criteria• Focus is on the bedside clinician

Current state prior to Sepsis-3

• Variety of terms• Septicaemia, septic, severe sepsis, septic

shock, sepsis

• 2 or more SIRS criteria to identify sepsis among those with suspected infection

• Organ dysfunction is key, but uncertain how to measure

• Multiple criteria for septic shock

Shankar-Hari et al., JAMA, 2016

Singer et al., JAMA, 2016

• Infection• Organ dysfunction• Life threatening• Dysregulated host response

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We have a definition for sepsis.

Criteria for the bedside

• Criteria for Infection?• Clinical diagnosis• Not the prevue of the Task Force

• Criteria for organ dysfunction?

Seymour et al., JAMA, 2016

Levy et al., Crit Care Med, 2003

• Use large electronic health record databases

• Identify those with suspected infection

• Study various existing OD criteria• SOFA score• LODS score• SIRS criteria

Developing sepsis criteria

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• No gold standard for sepsis

• We can’t rely on tests like sensitivity, specificity etc

• Use outcome more common in septic patients than healthy patients

Use of predictive validity

Outcome

Septic Not septic

Candidate clinical criteria

Primary cohort

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Patient characteristics

• CRISMA conducted primary analyses on UPMC data

• 2010 – 2012• Suspected infection patients• 12 hospitals• 4% mortality rate

Patient characteristics

Variable Threshold Units

Heart rate >90 BPM

Respiratory rate >20 BPM

Temperature <36 C

White blood cell count >12 k/uL

Temperature >38 C

White blood cell count <4 k/uL

Bands >10 %

Systolic blood pressure <=100 mmHg

Serum creatinine >=1.2 mg/dL

Pa02 / Fi02 ratio <=300

Platelets <=150 k/uL

Glasgow coma scale <15

Bilirubin >=1.2 mg/dL

Mechanical ventilation Present/absent

Vasopressors Present/absent

Vasopressors More than one

SIRS variables

SOFA variables

Additional candidate variables

Abnormal

Bicarbonate <=26 mmol/L

Saturation <=94 %

Glucose <=109 mg/dL

AST >=36 IU/L

ALT >=37 IU/L

INR >=1.4

Albumin <=2.5 g/dL

Troponin >=0.1 ng/mL

pH <=7.36

Lactate >=2.5 mmol/L

Fibrinogen <=300 mg/dL

ScvO2 <=69 %

0 50 100

Proportion (%) Normal

Missing

0 50 100 0 50 100

Proportion (%) Proportion (%)

All patients (N=74,453)

ICU patients (N=7,836)

Non-ICU patients (N=66,617)

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What do we already know at the bedside

• We built a baseline risk model using only age, demographics, race, co-morbidity

• Divide patients into deciles

• Compare validity within and across deciles

7,44

97,

4567,

515

7,37

27,

572

7,30

17,

523

7,39

07,

515

7,346

0

5

10

15

20

25

Deciles of baseline risk of in-hospital mortality

Ris

k of

in-h

ospi

tal m

orta

lity

No. of patients

1 2 3 4 5 6 7 8 9 10

Predictive validity of criteria

1 2 3 4 5 6 7 8 9 100.1

1

10

100

1000

10000

Fold

cha

nge,

in-h

ospi

tal m

orta

lity

SIRS ≥2 vs. SIRS <2

LODS ≥2 vs. LODS <2

SOFA ≥2 vs. SOFA <2

qSOFA ≥2 vs. qSOFA <2

Baseline risk (%)

ICU encounters N = 7,932

Decile of baseline risk of in-hospital mortality

Predictive validity of criteria

1 2 3 4 5 6 7 8 9 100.1

1

10

100

1000

10000

Fold

cha

nge,

in-h

ospi

tal m

orta

lity

SIRS ≥2 vs. SIRS <2

SOFA ≥2 vs. SOFA <2

LODS ≥2 vs. LODS <2

qSOFA ≥2 vs. qSOFA <2

Baseline risk (%)Median 0.2 0.8 1.4 1.9 2.4 2.9 3.4 3.9 4.6 6.2

Outside the ICU encounters N = 66,522

Decile of baseline risk of in-hospital mortality

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But SOFA is complex

• Sepsis criteria should be easy

• SOFA is complex, requires 12 variables, costly, range from 0 to 24 points

• Laboratory tests take time to result

• We need more simple parsimonious criteria for the bedside

quick Sepsis - Related Organ Failure Assessment

• 3 variables

• Measured near onset of infection

• No laboratory tests

• Studied in 72 � 6 hr windows around infection

qSOFA as a clinical prompt

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qSOFA as a clinical prompt

0.64 (0.62, 0.66)

<0.010.74 (0.73,

0.76)

<0.01 0.200.75 (0.73,

0.76)

0.01 <0.01 <0.010.66 (0.64,

0.68)

SIRS

SOFA

LODS

qSOFA

ICU encounters N = 7,932

AUROC in-hospital mortality

0.76 (0.75, 0.77)

<0.010.79 (0.78,

0.80)

<0.01 <0.010.81 (0.80,

0.82)

<0.01 <0.01 0.720.81 (0.80,

0.82)

SIRS

SOFA

LODS

Outside the ICU encountersN = 66,522

AUROC in-hospitalmortality

qSOFA

SOFA and LODS superior in the ICU

qSOFA similar to complex scores outside the ICU

qSOFA in external datasets

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Serum lactate as an adjunct

Missing

< 2.0 m

mol/ L

2.0 to

4.0 m

mol/L

≥ 4

.0 m

mol/L0

20

40

60

80

100

Pro

port

ion

in h

ospi

tal m

orta

lity

(%)

qSOFA = 0

qSOFA = 1

qSOFA = 2

qSOFA = 3

Serum lactate

1 2 3 4 5 6 7 8 9 100.1

1

10

100

Decile of baseline risk for in-hospital mortality

Fold

cha

nge,

in-h

ospi

tal

mor

talit

yqSOFA ≥2 vs. qSOFA <2(qSOFA + serum lactate) ≥2 vs. (qSOFA + lactate) <2

Baseline risk (%)Median

MinimumMaximum

1.0 1.9 2.7 3.4 4.2 5.0 5.8 6.7 7.9 10.4 0.6 1.4 2.3 3.0 3.8 4.6 5.4 6.2 7.3 8.9 1.4 2.3 3.0 3.8 4.6 5.4 6.3 7.3 8.9 30.3

Post hoc analyses

• Addressed missing data

• Measurement windows for qSOFA and SOFA• 24 hrs after infection• 6 hr window around infection

• Agreement of SOFA and qSOFA exceeded 70%

• Delta of 2 SOFA points same predictive validity

Conclusions

• In the ICU, the SOFA and LODS have greater

predictive validity than qSOFA or SIRS

• Outside the ICU, the qSOFA has similar predictive

validity to more complex scores

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Clinical criteria for sepsis• Infection plus 2 or more SOFA points above baseline

Prompt to consider sepsis outside the ICU

• Infection plus 2 or more qSOFA points

Controversies

• Where did “severe sepsis” go?

• Billing implications

• Was SIRS just left for dead?

• Delays in treatment if infection not suspected

• Why isn’t lactate in the criteria?

• Lacks face validity to not include

• Prospective evaluation?

• No association of new definitions with better outcomes

Controversies

• Change in SOFA – from what baseline value?

• Practical implementation is challenging

• Measure altered mentation?

• Multiple different scales available

• What to do if intermediate risk?

• qSOFA = 1

• Isn’t the AUROC a bad measure of clinical usefulness?

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Why Sepsis-3 provides clarity

• Speak the same language

• Redundant terms like severe sepsis are removed

• Objective criteria for organ dysfunction recommended

• Data driven

Why Sepsis-3 may lead to confusion

• Other criteria are available

• CMS, CDC surveillance criteria, RCT inclusion criteria

• Unclear how to chose time windows to measure criteria

• Blessing and curse of EHR data

• Suspected infection is a clinical decision• No check boxes proposed by Task Force

My approach outside the ICU

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My approach outside the ICU

Pt arrives

to ED

This looks like

pneumonia!

Did qSOFA

already occur?

Send lactate and

SOFA labs

Frequent re-

assessment

3-6 hr look back

Sepsis

My approach inside the ICU

Resources

www.jamasepsis.com

www.qSOFA.org

www.crisma.upmc.edu

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Questions