outline updates in sepsis background 2017 new definition ...€¦ · • new definition of sepsis...

1

Joshua Solomon, M.D.

Associate Professor of Medicine

National Jewish Health

University of Colorado Denver

Updates in Sepsis

2017

Outline• Background

• New Definition of Sepsis

• New Trials of EGDT

• Transfusions

• New sepsis bundle

• Survivors of sepsis

A 62 year-old female presents to the ED with fever, cough,

dyspnea. She has a history of diabetes and CHF.

T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.

CXR shows right lower lobe consolidation.

Wbc 14, Creatinine 2.1, Lactate 2.1

Epidemiology of sepsis

• Sepsis is a devastating medical condition

• Incidence has risen dramatically over the past 20 years

(3/1000 population)

• While in–hospital mortality is improving, 10th leading cause

of death in the United States

– mortality ranges from 30-50%

– >210,000 deaths/year

• Considerable impact on quality of life among survivors –

post critical illness syndrome

Angus DC, et al. Crit Care Med. 2001.

•0%

•5%

•10%

•15%

•20%

•25%

•30%

•35%

•40%

•45%

•0 •1 •5 •10 •15 •20 •25 •30 •35 •40 •45 •50 •55 •60 •65 •70 •75 •80 •85

Age

Mo

rta

lity

•Without Co-morbidity

•With Co-morbidity

•Overall

Mortality of Severe Sepsis by Age in the US

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

1,800,000

2001 2025 2050

Year

100,000

200,000

300,000

400,000

500,000

600,000

Severe Sepsis CasesUS Population

Se

ps

is C

as

es

To

tal U

.S. P

op

ula

tio

n/1

,00

0

Angus DC, et al. Crit Care Med. 2001.

Projected Incidence of Severe Sepsis in US 2001-2050

2

Bone et al. Chest 1992

Nidus of InfectionAbscessPneumoniaPeritonitisPyelonephritisCellulitis

Organism

Exotoxin

TSST-1Toxin-A

Structural ComponentTeichoic Acid AntigenPeptidoglycan, Endotoxin (LPS)Bacterial nucleic acids

Gut release ofendotoxin

Plasma

- Extrinsic / intrinsic pathways

- Protein C; S- TFPI

Complement Kinins

Coagulation

Monocyte-Macrophage

- TNF- Interleukins- Interferons- MIF- HMGB1

Cytokines

Endothelial Cells

Selectins, IcamsRenin-angiotensin systemProstaglandinsLeukotrienesProstacyclinThromboxaneEndothelin

Neutrophils

LysosomesOxygen free radicals

(superoxides)Granulocyte Colony

Stimulating Factor(G-CSF)

Cellular Dysfunction

Platelet Activating Factor

Nitric Oxide

Tissue Factor

Vasculature- Vasodilation- Vasoconstriction- Leukocyte aggregation- Endothelial cell dysfunction

Cellular Dysfunction

Organs- Dysfunction- Metabolic abnormalities

Myocardium- Depression- Dilatation

Shock

Refractory Hypotension Multiple Organ Dysfunction Recovery

Death

Pathogenesis of Septic Shock A 62 year-old female presents to the ED with fever, cough,


T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.



What is the patient’s diagnosis?

A. SIRS

B. Sepsis

C. Severe sepsis

D. Septic shock

SIRS

Sepsis

Severe Sepsis

Old Sepsis Definitions

Septic Shock

SIRS

Sepsis

Severe Sepsis


Septic Shock

Systemic Inflammatory Response Syndrome

2 or more of:

Temperature >380 or <360

Heart rate >90 beats/min

Respiratory rate >20 or PaCO2 < 32 mmHg

WBC >12,000, <4,000, or left-shift (>10%)

* Can result from a variety of insults (infection, trauma, pancreatitis, etc)

3

SIRS

Sepsis

Severe Sepsis


Septic Shock

SIRS

+

Suspected Infection

SIRS

Sepsis

Severe Sepsis


Septic Shock

All 3 criteria met within 6 hrs of each other

1.Documentation of suspected source of infection (“possible”)

2.SIRS

3.Organ dysfunction (need only one)

• SBP < 90 or MAP < 65 mm Hg within 1st hr

• Creatinine > 2 or urine output < .5 ml/kg/hr for > 2hr

• Bilirubin > 2 mg/dl

• Platelets < 100,000

• Coagulopathy (INR > 1.5 or PTT > 60 sec)

• Lactate > 2 mmol/L

SIRS

Sepsis

Severe Sepsis


Septic Shock

Severe Sepsis with:

Hypoperfusion despite “adequate” fluid resuscitation

(SBP < 90 or MAP < 65 mm Hg or 40% reduction from

baseline)

OR

Lactate > 4.0 mmol/L

SIRS

Sepsis

Severe Sepsis

Sepsis Definition 2017 (Sepsis 3)

Septic Shock

Quick SOFA

2 or more of

Resp Rate ≥ 22

Altered Mentation (GCS ≤13)

Systolic BP ≤ 100 mmHg

SIRS

Sepsis

Severe Sepsis

Sepsis Definition 2016

Septic Shock

Evidence of Infection

+

Change in baseline

SOFA score of ≥ 2

(assume baseline of 0)

SEPSIS

Clinical Handbook of Interstitial Lung DiseaseClinical Handbook of Interstitial Lung Disease

Sequential Organ Failure Assessment (SOFA) Score

4

SIRS

Sepsis

Severe Sepsis

Sepsis Definition 2016

Septic Shock

Vasopressors to maintain MAP ≥65

mmHg

And

Lactate > 2 mmol/L despite volume

resuscitation



T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.



What is the patient’s diagnosis (old definition)?A. SIRS

B. Sepsis

C. Severe sepsis

D. Septic shock



T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.



What is the patient’s diagnosis (old definition)?A. SIRS

B. Sepsis

C. Severe sepsis

D. Septic shock



T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.



What is the patient’s diagnosis (new definition)?A. Not Septic

B. Sepsis

C. Septic shock



T 102, HR 130, RR 24, BP 100/50, SaO2 = 94% on 6L.



What is the patient’s diagnosis (new definition)?A. Not Septic

B. Sepsis

C. Septic shock





The patient’s blood pressure on recheck is 85/45. She is given 1.5 L of saline but remains hypotensive (She weighs 75 kg)

What are the next best steps?A. Get blood cultures

B. Give broad spectrum antibiotics

C. Place a central line to measure CVP

D. A and B

E. All the above

5

Prompt Administration of Antibiotics Saves Lives

0

20

40

60

80

100

<0.5 .5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36

Kumar. Crit Care Med 2006

% S

urv

ivin

g

Time to Antibiotic Administration (hrs)

N = 2731 patients

10 hospitals, 14 ICUs

Prompt Administration of Antibiotics Saves Lives

0

20

40

60

80

100

<0.5 .5-1 1-2 2-3 3-4 4-5 5-6 6-9 9-12 12-24 24-36

Kumar. Crit Care Med 2006

% S

urv

ivin

g

Time to Antibiotic Administration (hrs)

Each hour of delay is associated

with an 8% decrease in survival

NEJM November 8, 2001; 345:1368-77.

• Has become a de facto standard

of care for the last 14 years for

how to resuscitate patients in

severe sepsis and septic shock.

• Has led to sepsis “bundles” of

care

– 3 hour bundle

– 6 hour bundle

Early Goal Directed TherapySevere Sepsis or

Septic Shock

CVP

MAP

SvO2

Goals

Met ?

IV Fluids

Vasopressors

< 8 mm Hg

8-12 mm Hg

< 65 mm Hg

> 65 mm Hg

Transfuse blood until

Hct > 30%

< 70%

> 70%

Dobutamine

< 70%

> 70%

No

ICU AdmissionYes

Rivers. NEJM 345:1368-1377,2001

0

10

20

30

40

50

60

In-hospital 28 Day 60 Day

Control

EGDT

**

*

Mort

ality

Rivers. NEJM 345:1368-1377,2001

**

* p<0.05

** p<0.01

Early Goal Directed Therapy - Mortality

2015 UPDATE

• 3 major large randomized trials

• Looking to determine if there REALLY is any benefit to using

the approach of EGDT vs. “usual care” in patients with septic

shock

PROCESS TRIAL

PROMISE TRIAL

ARISE TRIAL

6

ProCESS Trial

N Engl J Med 2014;370:1683-93.

ProCESS trial

• In 31 EDs across USA, randomly assigned patients with

septic shock to one of three groups for 6 hr of

resuscitation (1341 patients):

– Protocol-based EGDT

– Protocol-based standard therapy that did not require

placement of CVP, inotropes, or blood transfusions

– Usual care

Early Goal Directed TherapySevere Sepsis or

Septic Shock

CVP

MAP

SvO2

Goals

Met ?

IV Fluids

Vasopressors

< 8 mm Hg

8-12 mm Hg

< 65 mm Hg

> 65 mm Hg

Transfuse blood until

Hct > 30%

< 70%

> 70%

Dobutamine

< 70%

> 70%

No

ICU AdmissionYes

Rivers. NEJM 345:1368-1377,2001

Shock index = HR/SBP

Values ≥ 0.8 suggestive

of shock

• 60-day mortality

– Protocol EGDT: 21%

– Protocol standard therapy:

18.2%

– Usual care: 18.9%

• Relative Risk of death:

– Protocol v. usual care: 1.04

(0.82-1.31, p=0.83)

– EGDT v. prot. standard: 1.15

(0.88-1.51, p=0.31)

ProCESS: Conclusions

• “In our multicenter, randomized trial, in which patients

were identified early in the ED as having septic shock

and received abx and other non-resuscitation aspects of

care promptly, we found no significant advantage,

with respect to mortality or morbidity, of protocol-

based resuscitation over bedside care provided

according to the treating physician's judgment.

• We also found no significant benefit of the mandated

use of central venous catheterization and central

hemodynamic monitoring in all patients.”

7

• Enrolled 1600 patients at 51 centers to EGDT vs usual care in

Australia and New Zealand

• Primary outcome:

– 90-day mortality

• 90-day mortality:

– EGDT: 18.6%

– Usual care: 18.8% ( P=0.90 )

• EGTD had more vasopressors, RBC transfusions and dobutamine

• Pragmatic randomized trial of 1260 patients in 56 hospitals in

England

• Patients with early septic shock were randomized to receive either:

– 6 hours of Early Goal-directed Therapy (EGDT)

– 6 hours of usual care

• 90 day mortality the same (29.5% vs 29.2%)

• EGDT had more IVF, vasoactive drugs, RBC

• EGDT had worse organ failure scores, more days with CV support,

longer ICU stays

Study Setting Patients EGDT Usual Care Protocol

Based

Rivers Single Center 263 44.3 56.9

ProCESS

ARISE

ProMISE

% Mortality

Study Setting Patients EGDT Usual Care Protocol

Based

Rivers Single Center 263 44.3 56.9

ProCESS USA (31) 1341 21 18.9 18.2

ARISE Aus/NZ (51) 1591 18.6 18.8

ProMISE England (56) 1251 29.5 29.2

% Mortality

Study EGDT Usual Care EGDT Usual Care

Rivers 27 30 100 NA

ProCESS 55 44 97 58

ARISE 66 58 98 62

ProMISE 53 46 99 51

% with CVC% on Pressors

CVP is useless for assessing volume status

Marik P. Chest. 2008;134(1):172-178.Shippy CR. Crit Care Med 1984. 12:107-112.

8

CVP is useless for assessing volume status

Shippy CR. Crit Care Med 1984. 12:107-112.









D. A and B

E. All the above









D. A and B

E. All the above




Wbc 14, Creatinine 2.1, Lactate 2.1, Hgb 8


What should we do about fluids?A. Give saline 30cc/kg based on CMS guidelines

B. Give fluids until you think she’s had enough

C. Give blood to volume expand and improve oxygenation

D. A and B

E. All the above

Study Setting EGDT Usual Care

Rivers Single Center 4.4 3.9

ProCESS USA (31) 2.8 2.2

ARISE Aus/NZ (51) 2.5 1.7

ProMISE England (56) 2.2 2.0

After enrollment (L)

Fluid Administration

Study Setting EGDT Usual Care EGDT Usual Care

Rivers Single Center 4.4 3.9 7.4 6.9

ProCESS USA (31) 2.8 2.2 4.9 4.3

ARISE Aus/NZ (51) 2.5 1.7 5.1 4.3

ProMISE England (56) 2.2 2.0 4.2 4.0

After enrollment (L) Total in 6hrs (L)


9

Study EGDT Usual Care

Rivers 64.1 18

ProCESS 14.4 7.5

ARISE 13.6 7.0

ProMISE 8.8 3.8

% Transfused

Blood Administration

TRISS Study

•Multicenter randomized

controlled trial

•998 patients with septic shock

•Transfused for Hgb < 9 or Hgb

< 7

•No benefit to higher Hgb


Summary and Additional Notes

• Starch is bad – leads to renal failure and increased mortality

• Albumin appears to be safe but no benefit over crystalloid

(ALBIOS and SAFE studies)

• Don’t use blood to volume expand

• Crystalloids are best studied

– Give a minimum of 30 cc/kg in first 6 hrs (CMS guidelines)

– Most patients needed at least 4L in multicenter trials

– Use your clinical skills to determine the optimum amount

• LR may be better than saline (pH 3-6, chloride 150)






What should we do about fluids?A. Give saline 30cc/kg based on guidelines



D. A and B

E. All the above






What should we do about fluids?A. Give saline 30cc/kg based on guidelines



D. A and B

E. All the above

Septic Shock Bundle

0 6 hr3 hr

1. measure lactate level

2. obtain blood cultures prior to

antibiotics

3. administer broad spectrum

antibiotics

4. 30 cc/kg crystalloid for

hypotension or lactate ≥4

1. apply vasopressors for

hypotension that does not respond

to initial fluid resuscitation

(MAP≥ 65)

2. re-assess volume status and

tissue perfusion and document

findings.*

3. Re-measure lactate if initial level

was elevatedPhysical exam or 2 of

CVP

ScVO2

Echo

Dynamic assessment

10

Sepsis Survivors

• Of those who lived independently prior to sepsis:– 1/3 die by 6 months

– 1/3 of 6 month survivors have not returned to independence

– 45% of those with problems at 6 m die or continue with problems at 1y

Yendi et al. Crit Care 2016

Jutte et al. SRCCM 2015

Conclusions • New definitions of sepsis and septic shock

• No need for routine CVL and CVP

• Less transfusion (target hg > 7)

• ? Protocol to use but EGDT is not necessary

• Crucial points – early recognition, early antibiotics, lot of fluid

• Survivors of sepsis have a tough road ahead of them

outline updates in sepsis background 2017 new definition ...€¦ · • new definition of sepsis...

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