definicions, criteris diagnòstics i estadis de la sèpsia ... · definicions, criteris...

Definicions, criteris diagnòstics i estadis de la sèpsia

Surviving Sepsis Campaign Bundles

Ricard Ferrer

Intensive Care Department

Mutua Terrassa University Hospital

Barcelona. SPAIN

Definiciones

INFECCIÓN SIRS

SEPSIS PANCREATITIS

GRANDES

QUEMADOS

POLITRAUMA

SEPSIS GRAVE

SHOCK

SÉPTICO

NEJM 2002;347:966-7

Epidemiología y Mortalidad

Crit Care Med 2013; 41:1167–1174

Projected Incidence of Severe Sepsis in the US: 2001 - 2050

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 Cases

US Population

Sep

sis

Case

s

To

tal U

.S.

Po

pu

lati

on

/1,0

00

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

Epidemiology of Severe Sepsis

0

20

40

60

80

100

120

EPISODES

100.000 res/y

France Australia UK Spain

INCIDENCE OF SEVERE SEPSIS

Brun-Buisson C et.al Intensive Care Med. 2004;30(4):580-8.

Finfer S et al. Intensive Care Med. 2004;30(4):589-96.

Padkin A et al. Crit Care Med. 2003;31(9):2332-8.

Esteban A et al. Crit Care Med. 2004.

MORTALITY: 28 to 50%

Crit Care Med 2007; 35:1284–1289

Incidence Severe sepsis: 104/100.000 res/y

Only 32% received intensive care

Incidence Septic Shock: 31/100.000 res/y

Mortality 20.7% - 45.7%

Local Data: Catalonia

SCCM 2014

17% relative reduction in 5 years ICD 9th-CM, severe sepsis

La sepsis es una de las enfermedades más frecuentes pero menos reconocidas del

mundo

1. INTRODUCCIÓN MEDICINA INTENSIVA

Entre 20-30 millones de

personas en todo el mundo son

afectadas cada año. De las cuales

8 millones mueren.


Cada 4 segundos

alguien muere por sepsis en el

mundo


Crit Care Med 2009; 37: 1268–1274

Mortality (%)

ICU 15.5

Hospital 28.3

1 Year 40.9

2 Year 44.9

Quality of life (EuroQol-5D)=

Crit Care Med 2009; 37: 1268–1274

Immune cells

Mediators

Inflammation

Pathogenesis of Sepsis

Pattern recognition receptors (PRR)

Pathogen-associated molecular patterns (PAMPs)

Adaptive:

Control of infection

Exaggerated:

Necrotic Cell Death

Damage-associated molecular patterns (DAMPs) or ALARMINS

Infection

. . .

. .

. .

.

. . .

. . .

. .

Host immune response to sepsis:

Sepsis

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Hotchkiss et al. Nature Reviews Immunology 13, 862–874 (2013)

Immunomodulators could treat sepsis by inducing, enhancing or supressing the immune response

ENDOTOXIN (PAMP) MACROPHAGE

TLR-4 (PRR)

PRO-INFLAMMATORY

CYTOKINES

IL-1, IL-6, TNFα

HMGB1

COMPLEMENT

ACTIVATION

ANTI-INFLAMMATORY

CYTOKINES

IL-10, IL-11…

LIPID MEDIATOR FACTORS

PG, LEUCOTRIENS…

PAF

OXIGEN RADICALS

ANANDAMIDE…

VASODILATATION

HYPOTENSION

ENDOTHELIAL

CELLS

THROMBIN

THROMBOTIC

RESPONSE

↑ AGGREGATION

PAI-1

FIBRINOLISIS

INHIBITION

DIC

COAGULOPATHY

LYMPHOCYTES

TISSUE FACTOR

↑ Treg %

Apoptosis

NEUTROPHILS ANTINFECTIOUS

RESPONSE

MODERATED PRO-INFLAMMATORY RESPONSE: BENEFICIAL SEVERE PRO-INFLAMMATORY RESPONSE: SEPTIC SHOCK

Cell Death and Multi-organ failure

Immuno-paralysis

SEVERE ANTI-INFLAMMATORY RESPONSE: HARMFUL MODERATED ANTI-INFLAMMATORY RESPONSE:BENEFITIAL

MICROVASCULAR

DYSFUNCTION

CAPILARY LEAK

INTERSTICIAL EDEMA

NITRIC OXIDE

SEPSIS Heterogenicity

INFECTION

Virulence of Microorganisms

Load

Organ Involved

HOST RESPONSE:

SIRS

Genetic Background

Comorbidities

Physiological Reserve

Inmunological Status

Site of Infection

Lungs

Urinary Tract

Abdomen

Endovascular Catheters

Bilis

Skin and soft tissue

Meningitis

A

A

A

G

G

G C

C

C

T

T

T

Single Nucleotide Polimorphism

C G A

A

G

G

G C

C

T

T

C

IL10 -208 T/C SNP

-209

-208

-207

-206

Genetic Polymorphisms and Severe Sepsis

Meningococcemia; Severe sepsis

Meningococcemia; Severe sepsis

Severe Sepsis

PAI-1

Factor V Leiden

Protein C; Fibrinogen

Meningococcemia; Septic Shock

Severe Sepsis

Severe Sepsis, Meningococcemia

Severe sepsis

TNF locus

IL-18

IL-10

IL-6

Meningococcemia; Pneumococcemia

FCgRII Receptor

Meningococcemia, Pneumococcemia

Severe sepsis

Mannose Binding Lectin

Susceptibility and/or Outcome Gene

Septic Shock, Legionnaire’s Disease

Septic Shock

Septic shock, Pneumococcemia

Toll-Like Receptors

CD14

IRAK-1; Mal; IkBa

Severe Sepsis

Viral Pneumonia

Severe Sepsis

IL-1 locus

IL-4

Caspase 12

Phenotype: PIRO concept

Predisposition

Insult (Infection)

Response

Organ Dysfunction

Genetic susceptibility Coexisting health complications

Pathogen, toxicity and sensitivity Location and compartmentalization

Increased biomarkers or biomediators Manifested physiologic symptoms

Number of failing organs

Carrigan Clin Chem 2004;50:1301

Phenotype: SOFA score

From 0 to 24: If <4 mortality 9% ;If >15 mortality 90%

Patients don’t suddently deterioriate, healthcare professionals suddently notice!

Patients don’t suddenly

deteriorate, healthcare

professionals suddenly notice!

Recognition of Severe Sepsis

Infection SIRS:

Sepsis Severe Sepsis

Septic Shock

MODS

Are any two of the following SIRS criteria present and new to the patient?

Heart rate > 90 beats/min Respiratory rate > 20/min

Temperature < 36.0 or > 38.3C Acutely altered mental state

Blood glucose > 7.7 mmol/L (in absence of diabetes) White cell count < 4 or > 12 x 109/L

Is there a clinical suspicion of new infection?

Cough/sputum/chest pain Dysuria

Abdominal pain/distension/diarrhea Headache with neck stiffness

Line infection Cellulitis/wound/joint infection

Endocarditis

Is there evidence of any organ dysfunction?

Systolic BP < 90/mean < 65 mmHg Urine output < 0.5 mL/kg/h for 2 h

Lactate > 2 mmol/L after initial fluids Creatinine > 177 umol/L

INR > 1.5 or aPTT > 60 s Platelets < 100 x 109/L

Bilirubin > 34 umol/L SpO2 > 90% unless O2 given

If YES, patient has SIRS

If YES, patient has Sepsis

If YES, patient has Severe Sepsis

Daniels R. J Antimicrob Chemother. 2011;66(Suppl 2):ii11–ii23.

Recognition of Severe Sepsis

SIRS criteria at ICU admission

Outcome according SIRS criteria at ICU admission

87%

Which is the useful marker for the early

recognition of sepsis?

IL-6 CRP

PCT WBC

TNF-α erythrocyte

sedimentation

Procalcitonin as a diagnostic test for

sepsis in critically ill adults and after

surgery or trauma:

A systematic review and meta-analysis.

Global diagnostic OR for PCT

2966 pts

25 studies

15.7 (9.1-27.1)

Risk for positive PCT test in

infected pts was 16-fold higher

than in non-infected pts.

Global diagnostic OR for CRP

1322 Pts

15 studies

5.4 (3.2-9.2)

Q* 0.78 vs. 0.71 p = .02

Uzzan et al.

Crit Care Med 2006; 34:1996–2003

Serial Determinations: Early sepsis recognition

Castelli et al. Crit Care Med 2009

INFE

CTI

ON

Lactic Acidosis

Mizock BA, Falk JL. Crit Care Med. 1992;20:80-95.

Glycogen

Glucose Pyruvate

Lactate

Citric

Acid

Cycle

CO2

H2O

(Cytoplasm) (Mitochondria)

Anaerobic Glycolysis

1 Glu + 2 ADP + 2 Pi

2 Lactate + 2 ATP

1 Glu + 6 O2 + 38 ADP + 38 Pi

6 CO2 + 6 H20 + 38 ATP

O2

Aerobic Glycolysis

+ Hydrogen ion

Serum Lactate and Mortality in Severe Sepsis

• Initial serum lactate

evaluated in 839 adults

admitted with severe

sepsis.

Mikkelsen ME, Miltiades AN, Gaieski DF et al. Crit Care Med. 2009;37:1670-7.

Low Int High

Shock Non-Shock

28-D

ay

Mo

rta

lity

(%

)

50

45

40

35

30

25

20

15

10

5

0

p < 0.001

p = 0.001

p = 0.022

p = 0.024

High initial serum lactate associated with ↑ mortality regardless of presence of shock (hypotension despite fluid resuscitation).

Low Int High

Improving Lactate: a Good Prognostic Sign

Bakker J, Gris P, Coffernils M et al. Am J Surg. 1996;171:221-6.

8

6

4

2

0 INITIAL +8h +16h +24h FINAL

Time

Lacta

te (

mm

ol/L

)

Survivors

Non-survivors p < 0.05

p < 0.05

p < 0.01

Pillars of Sepsis Treatment

ABX Source Control EGDT

Lactate Radiology

YOUR speed is LIFE!

Canine Model of Human Septic Shock:

Synergy between Treatments

Natanson C. JAP 1990

Suvirval according TTM:

-No TTM= 0%

-Only ABX= 13%

-Only HMDC support= 13%

-Both= 43%


ABX

Lactate Radiology

YOUR speed is LIFE!

time from hypotension onset (hrs)

fraction o

f to

tal patients

0.0

0.2

0.4

0.6

0.8

1.0 survival fraction

cumulative antibiotic initiation

Early appropiate antibiotic treatment

Kumar A et al. Crit Care Med 2006;34:1589-96

Median time to

effective

antimicrobial therapy

was 6 hrs

2.154 patients with septic shock

Mortality Risk with Increasing Delays in Initiation of Effective Antimicrobial Therapy

Kumar A et al. Crit Care Med 2006;34:1589-96

Effectiveness of Treatments. Propensity Score

OR and 95% CI

Broad spectrum AB:

Fluid challenge#

0-1 Hour 1-3 Hour 3-6 Hour Previous AB No AB first 6H

Steroids in septic shock

APC in MOF

Fluid challenge, only severe sepsis

Ferrer R et al. AJRCCM 2009;180:861–866

2.796 patients with severe sepsis or septic shock

Time to Treatment. Antibiotics

Ferrer et al. Submitted Annals of Internal Medicine

25.089 patients with severe sepsis or septic shock

Predicted Mortality with 95% CI0

.1

.2

.3

.4

Ho

spita

l M

ort

alit

y

0 1 2 3 4 5 6

Time to ABX, hours

Severe sepsis Septic shock

Patient: North America, one baseline organ failure, and community acquired infection

Hospital Mortality by Time to ABX

Appropiate antibiotics

Crit Care Med 2003;31:2742–2751

ICU

HOSPITAL

HEALTHCARE

COMMUNITY

ALERT: New antibiotics are needed

RIS

K O

F R

ES

ISTA

NC

E

RIS

K O

F IN

AP

PR

OP

RIA

TE

TR

EA

TM

EN

T


EGDT

Lactate Radiology

YOUR speed is LIFE!

Rivers et al. N Engl J Med 2001; 345: 1368-1377

• First 6 hours

• Control: Usual care ED + ICU

• TTM:

• Protocol in the ED, later

transfer to ICU.

• Continuous ScvO2

• ScvO2 goal

n= 263; 1 ED

EGDT in patients with septic shock or lactate > 4

T C RRR NNT p

Hospital mortality 31% 47% 34% 6 0.009

60d mortality 44% 57% 22% 8 0.03

Early goal-directed therapy

EGDT in patients with lactate >4 and no hypotension

(cryptic shock)

T C RRR NNT p

Hospital mortality 20% 60,9% 67% 2.5 0.004

Quantitative Resuscitation in sepsis:

Meta analysis

Jones A et al. Crit Care Med 2008; 36:2734–2739

Jones A et al. JAMA 2010;303(8):739-46

Different Goals.

In both arms:

• All patients treated in ED.

• ICU was blinded.

• Same catheter inserted.

• Same protocol.

• Same treatments:

• Fluids

• Vasopressors

• Inotropes

• PRBC

n= 300; 3 ED

Jones A et al. JAMA 2010;303(8):739-46

Different Goals, same administered treatments

Jones A et al. JAMA 2010;303(8):739-46

Different Goals, same morbidity and mortality


Source Control

Lactate Radiology

YOUR speed is LIFE!

Timing of Source Control

APACHE II

Score

Relaparotomy

< 48 hours

Relaparotomy

> 48 hours

P

0 – 10 0 % 25 % 0.09

11 – 15 0 % 33 % 0.02

16 – 20 0 % 78 % 0.002

21 – 25 57 % 100 % 0.02

> 26 79 % 94 % 0.2

Total 28 % 77 % 0.0001

Mortality after surgery for persisting

intraabdominal infection

Koperna et al. World J Surg 2000

Timing of surgery in NSTI

Wong CH et al., J Bone Joint Surg Am 2003, 85-A: 1454-60.

Time-dependent Diseases

AMI STROKE TRAUMA SEPSIS

Clinical

Recognition Easy Easy Easy Complex

Population Homogeneous Homogeneous Heterogeneous Heterogeneous

Biomarker YES NO NO YES/NO

Complex

Treatment

Algorithms

++ ++ +++ +++

Multidisciplinary

Approach + ++ +++ +++

Well

established

guidelines

+++ +++ +++ ++

Code Yes Yes Yes +/-

SSC 2013 Care Bundles

• WITHIN 3 HOURS OF SEVERE SEPSIS:

1) Measure lactate level

2) Obtain blood cultures prior to antibiotics

3) Administer broad spectrum antibiotics

4) Administer 30ml/kg crystalloid for hypotension or lactate

≥4mmol/L

• WITHIN 6 HOURS OF INITIAL SYMPTOMS FOR SEPTIC SHOCK:

5) Apply vasopressors (for hypotension that does not respond to

initial fluid resuscitation to maintain a mean arterial pressure

≥65mmHg)

6) In the event of persistent arterial hypotension despite volume

resuscitation (septic shock) or initial lactate ≥4 mmol/L (36mg/dl):

- Measure central venous pressure (CVP)

- Measure central venous oxygen saturation (ScvO2)

7)Remeasure lactate if initial lactate was elevated

Conclusions

1. Sepsis is time-dependent: YOUR speed is LIFE

2. New antibiotics are needed, specially for the

nosocomial environment.

3. Despite important investment and lots of

clinical trials we do not have an effective drug

for sepsis.

4. For future studies is important to target specific

populations: Organ dysfunctions, biomarkers,

genotype.

5. Meanwhile is important to optimize the

available treatments.

[email protected]

Ricard Ferrer

Intensive Care Department

Mutua Terrassa University Hospital

Barcelona. SPAIN

definicions, criteris diagnòstics i estadis de la sèpsia ... · definicions, criteris...

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