Sepsis or Severe Sepsis? - American College of Physicians · • Systemic Inflammatory Response...

Sepsis or Severe Sepsis? Is there a right thing, and how do we do it?

Steven Q Simpson, MD, FCCP, FACP

Professor of Medicine

Division of Pulmonary and Critical Care

University of Kansas

Disclosures

No commercial interests to disclose

Founder of Midwest Critical Care

Collaborative

Founder of the Kansas Sepsis Project

Participant 2016 update, Surviving Sepsis

Campaign Guidelines

Dissenting opinion on Sepsis-3 in CHEST

Kansas: Exemplar of Rural America

Objectives

1. Discuss definitions of sepsis and what they

mean

2. Discuss the role of Early Goal Directed

Therapy in sepsis

3. Discuss CMS measures and their role in

improving sepsis care

21st Century Sepsis Teaching?

“as the physicians say it happens in hectic fever,

that in the beginning of the malady it is easy to

cure but difficult to detect, but in the course of

time, not having been either detected or treated in

the beginning, it becomes easy to detect but

difficult to cure”

Niccolò Machiavelli

The Prince – 1513 or 1532

What is Sepsis?

Life threatening organ dysfunction due

to a dysregulated host response to

infection

What is Sepsis?

Life threatening organ dysfunction due

to a dysregulated host response to

infection

Hospital Case

•72 y.o. man, 3 days post-op from ureteral stent

placement; Foley in place

• Nurse finds him with flank pain and fever,

mild confusion (previously oriented x 4)

•Hx of CAD, HTN

•Meds include terazosin, atorvastatin,

metoprolol

•BP 105/43, P 117, R 21, T 39.1o , SpO2 87%

•Exam: left CVA tenderness, BPH

ACCP/SCCM Consensus Definitions

• Infection - Inflammatory response to

microorganisms, or

- Invasion of normally sterile

tissues

• Systemic Inflammatory

Response Syndrome

(SIRS)

- Systemic response to a variety of

processes

- 2 or more SIRS criteria

•Sepsis – Infection plus

2 or more SIRS criteria

• Severe Sepsis – Sepsis

– Organ dysfunction

• Septic shock – Sepsis

– Hypotension despite fluid

resuscitation

Bone RC et al. Chest. 1992;101:1644-55.

SIRS:

Systemic Inflammatory Response Syndrome

• SIRS: nonspecific insult

≥ 2 of the following:

– Temperature

> 38o C or < 36o C

– HR > 90 beats/min

– Respirations > 20/min

– WBC > 12,000/µL,

< 4,000/µL, or >10%

immature neutrophils (bands)

Adapted from: Bone RC et al. Chest. 1992;101:1644-55.

Opal SM et al. Crit Care Med. 2000;28:S81-2.

SIRS

Acute Organ Dysfunction as the Hallmark of

Severe Sepsis

Hypotension SBP < 90 MAP < 65

Oliguria - < 20 mL/hr Anuria

Creatinine △ (>0.5 mg/dL)

↓Platelets (< 100k) ↑(INR>1.5, PTT>60 sec)

↑ D-dimer

Altered Consciousness

Confusion Psychosis

Tachypnea PaO2 <70 mm Hg

SaO2 <90% PaO2/FiO2 < 300

T. Bilirubin > 4 mg/dL

Lactic acidosis

Sepsis: What Are We Talking About?

Roger C. Bone, MD

•ICD-9: “septicemia”

•Positive blood cultures

•Multiple positive blood

cultures

•Positive blood cultures +

hypotension

•Syndrome: how shall we

define it?

The Third International Consensus Definitions

for Sepsis and Septic Shock (Sepsis-3)

Definition:

Sepsis is life threatening organ dysfunction

caused by a dysregulated host response to

infection

Drops the term “severe sepsis”

Drops the use of SIRS and infection + SIRS

Condition Sepsis-2 Sepsis-3

Sepsis Infection + SIRS Infection + ∆ SOFA ≥ 2

Severe Sepsis Infection + SIRS + organ dysfunction

NON-EXISTENT

Septic Shock Infection + Unresponsive Hypotension*

Infection + Unresponsive Hypotension* + Serum Lactate > 2 mmol/L

The Third International Consensus Definitions

for Sepsis and Septic Shock (Sepsis-3)

*Hypotension that does not respond to volume infusion and requires vasopressor administration

SOFA Score 1 2 3 4

Respiration PaO2/FiO2

< 400 < 300 < 200

With respiratory support

< 100 with respiratory

support

Cardiovascular Hypotension

MAP < 70 mm Hg

Dopamine ≤ 5 or dobutamine, any

dose

Dopamine > 5 or epinephrine or norepinephrine

≤ 0.1

Dopamine > 15 or epinephrine

or norepinephrine

> 0.1

Liver Bilirubin (mg/dL) 1.2 – 1.9 2.0 – 5.9 6.0 – 11.9 > 12.0

Renal Creatinine (mg/dL) or urine output

1.2 – 1.9 2.0 – 3.4 3.5 – 4.9 or

< 500 mL/24 hr ≥ 5.0 or

< 200 mL/24 hr

Coagulation Platelets x 103/mm3 < 150 < 100 < 50 < 25

CNS Glasgow Coma Scale 13 - 14 10 - 12 6 - 9 < 6

Quick SOFA

• Also known as qSOFA

• Any two of:

- Glasgow Coma Scale < 15

- Respiratory rate ≥ 22/min

- Systolic blood pressure ≤ 100 mm Hg

ROC Results

ROC Curves & Diagnostic

Accuracy Excellent

Fair-Good Worthless

1 – specificity (False Positive Rate)

Sen

siti

vity

(Tr

ue

Posi

tive

Rat

e)

This is NOT the probability of the OUTCOME, if the TEST is positive. It is the probability that the TEST is positive in someone who had

the OUTCOME and negative in someone without it.

i.e.

This is NOT the probability of death if qSOFA or SIRS is positive. It is the probability that qSOFA or SIRS was present in those who

died and not present in those who survived.

“SIRS is too non-specific”

“I make love to my wife and I get SIRS”

“Hopefully, more than once!”

Jean-Louis Vincent

Bayes’ Theorem

P(D|T) = P(T|D)P(D)

P(T|D)P(D) + P(T|D’)P(D’)

Psepsis | SIRS ≅ PSIRS | sepsis x Psepsis in group

Bayes’ Theorem

Psepsis | SIRS ≅ PSIRS | sepsis x Psepsis in group

PSIRS

Likelihood Ratio / Fagan Nomogram “The essence of the Bayesian approach is to provide a mathematical rule explaining

how you should change your existing beliefs in the light of new evidence.”

Post-test probability of a disease is dependent on:

1. the pre-test probability of disease

2. characteristics of the test (likelihood ratio)

LR + = sensitivity / (1 – specificity)

LR - = (1 – sensitivity) / specificity

Treatment threshold

Test threshold

Fagan TJ. N Engl J Med 1975;293:257.

Criticizing SIRS for being too

sensitive a test to diagnose sepsis

in all comers is like criticizing a

hammer for being the only tool in

your toolbox.

SIRS Infection Suspect

SEPSIS

qSOFA Infection Suspect

SEPSIS

Infection Syndromes

Pneumonia – cough, purulent sputum, pleuritic chest

pain, consolidation

Cellulitis – redness, tenderness, advancing margin

Pyelonephritis – flank pain, costophrenic angle

tenderness, urinary leukocytosis

Peritonitis – abdominal pain, ileus, rebound

tenderness, rigidity

Possible BSI from indwelling catheter

Hospital Case

•72 y.o. man, 3 days post-op from ureteral stent

placement; Foley in place

• Nurse finds him with flank pain and fever,

mild confusion (previously oriented x 4)

•Hx of CAD, HTN

•Meds include terazosin, atorvastatin,

metoprolol

•BP 105/43, P 117, R 21, T 39.1o , SpO2 87%

•Exam: left CVA tenderness, BPH

Early Goal Directed Therapy

Wanted Dead or Alive?

Rivers E, et al. N Engl J Med 345:1368 – 1377, 2001.

• Primary Endpoint: In hospital mortality; single center

• Secondary Endpoints:

- Resuscitation endpoints

- Organ dysfunctions

- Coagulation endpoints

- Healthcare resources

EGDT

NEJM 345:1368 – 77, 2001.

Lactate

> 4 mmol/L

or

Septic Shock

EGDT Initial Results

Rivers E, et al. N Engl J Med 345:1368 – 1377, 2001.

EGDT

NEJM 345:1368 – 77, 2001.

ARISE

ProCESS ProCESS

ARISE

ProMISE

HOWEVER – I2 = 57%

SUBSTANTIAL HETEROGENEITY

Cut and Dried?

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Power of randomization

Properties of the normal distribution

Two Concepts to Remember

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Intention to Treat Analysis

Inclusion of all randomized patients in each

group

Helps overcome

– Protocol non-compliance

– Missing data

Not intended for

– Patients who already meet endpoint at inclusion

Perspect Clin Res. 2011 Jul-Sep; 2(3): 109–112.

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if hypotensive > 29 mL/kg > 30 mL/kg

> 1.95 L in 2.5

hours

Rivers, et al. ProCESS ARISE ProMISe

# per group 130, 130 445, 448, 458 792, 796 625, 626

Standard Rx

Mortality 46.5% 18.9% 18.8% 29.2%

EGDT

Mortality 30.5% 21.0% 18.6% 29.5%

APACHE II 20.4 20.7 15.8 18.0

ScvO2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12

ScvO2 > 70% 3, 3 222, 224, 229 346, 348 312, 313

Antibiotic

Time

92.4% in 6

hours

75% in 72

minutes

median 91

minutes

100% in 2.5

hours

Fluids Before

Randomizing

20-30 mL/kg,

if

hypotensive

> 29 mL/kg > 30 mL/kg > 1.95 L in 2.5

hours

ProCESS, ARISE, ProMISe

• EGDT, as originally defined, applied to patients

who meet the original criteria, does not add

survival benefit in centers adept at sepsis

management when patients are identified early,

given antibiotics and fluid boluses early.

EGDT vs Control:

Benefit Depends on Control

Group Mortality

Benefit when

Control Mortality >35%

EGDT inferior to

Lactate/CVP directed

therapy

Remaining Scientific Questions

How important is low ScvO2 in determining

MORTALITY from septic shock?

Should all patients with septic shock be

assessed for low ScvO2? (this means central

access in all)

For patients who actually have low ScvO2, is

some form of systematic approach

desirable?

Time will tell!

CMS Measures

and

Quality Sepsis Care

“We’re from the Government

We’re here to help”

Surviving Sepsis Campaign Bundles

To be completed within 3 hours:

1. Measure serum lactate level

2. Obtain blood cultures prior to administration of

antibiotics (1C)

3. Administer broad spectrum antibiotics (1B, 1C)

4. Administer 30 mL/kg crystalloid for

hypotension or lactate ≥ 4 mmol/L

Surviving Sepsis Campaign Bundles

To be completed within 6 hours

1. Apply vasopressors (for hypotension that does not

respond to initial fluid resuscitation) to maintain a

mean arterial pressure (MAP) ≥ 65 mm Hg

2. In the event of persistent arterial hypotension despite

volume resuscitation (septic shock) or initial lactate ≥

4 mmol/L (36 mg/dL)

Measure central venous pressure (CVP)*

Measure central venous oxygen saturation (ScvO2)*

3. Re-measure lactate if initial lactate was elevated*

*Targets are: CVP 8 mm Hg, ScvO2 > 70%, lactate normal

CMS Core Measures: Simply Complicated

Within 3 hours of Presentation of

Severe Sepsis

1. Initial lactate level measurement

2. Broad spectrum antibiotics administered

3. Blood cultures drawn prior to antibiotics

4. Crystalloid fluid initiated

Within 3 hours of Presentation of

Septic Shock

1. Resuscitation with 30ml/kg crystalloid fluids

2. Evaluate the need for vasopressors

Did hypotension persist after fluid given?

NO

YES, continue on

Core Measure goals met, re-measure lactate within 6hrs

After fluid resuscitation, but within 6

hours of Presentation of Septic Shock

Re-assessment of volume status and tissue perfusion A focused exam including

• Vital signs

• Cardiopulmonary exam

• Capillary refill evaluation

• Peripheral pulse evaluation

• Skin examination

Must be performed and

documented by a Physician,

ARNP, or PA

2 out of 4 from the following:

CVP Bedside Cardio US ScvO2

Passive Leg Raise or Fluid Challenge

www.mwcritcare.org

www.kansassepsisproject.org

www.kansassepsisproject.org

Thank you!

ssimpson3@kumc.edu