Atenció Precoç al Pacient amb Sèpsia Greu

Ricard FerrerCritical Care Department

Mutua Terrassa University HospitalBarcelona. SPAIN

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

Recognition of Severe Sepsis

Resum

• Importància de l’atenció precoç.

• Reconeixement de la sèpsia:– Marcadors fisiològics.

– Biomarcadors

• Organització del tractament de la Sèpsia.

Importance of Early Recognition

Stages of Sepsis

Time to Treatment

Sepsis is Time Dependent

Microbes

Immune cells

Mediators

SystemicResponse

Pathogenesis of Sepsis

Pattern recognition receptors

(PRR)

Pathogen-associated molecular patterns

(PAMPs)

Organ Dysfunction in Severe Sepsis

Infection

.... ...

..

..

. ...

.

Systemic response:Genetic make-upPhysiologic reserve

Diffuse Endothelial Activation

Microvascular DysfunctionRegional mis-matchof O2 supply/demand

Mitochondrial dysfunction

Hypoxic Hypoxia

Cytopathic Hypoxia

Fink. Crit Care Med 2002;6:491 Brealey. Lancet 2002:360:219 Ince. Crit Care Med 1999;27:1369

Stages of sepsis: The Sepsis Continuum

Adapted from Bone RC, Balk RA, Cerra FB et al. Chest. 1992;101:1644-55.

Infection SIRS: Sepsis

Severe Sepsis

Septic Shock MODS

Infection

.... ...

..

..

. ...

.

↑ Microvascular Dysfunction

Time is Tissue

Rangel‐Frausto JAMA 1995;273:117

3768 pts3 ICU, 3 wards

SIRS2527 (68%)

Sepsis649 (26%)

Severe Sepsis467 (18%)

Septic Shock110 (4%)

78 (71%)Previously classified as

SIRS, sepsis or Severe sepsis

271 (58%)Previously classified as

SIRS or sepsis

285 (44%)Previously classified as

SIRS

Continuum from SIRS to sepsis to severe sepsis to septic shock

21% Infected

11% Severe sepsis or septic shock

Septic shock

Severe sepsis

SIRSInfection

time from hypotension onset (hrs)

fract

ion

of to

tal p

atie

nts

0.0

0.2

0.4

0.6

0.8

1.0 survival fractioncumulative antibioticinitiation

Early antibiotic treatment

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

Median time to effective

antimicrobial therapywas 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% CIBroad spectrum AB:

Fluid challenge#

0-1 Hour1-3 Hour3-6 HourPrevious ABNo 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. ESICM 2011, Abstract 139

25.089 patients with severe sepsis or septic shock

Predicted Mortality with 95% CI0

.1

.2

.3

.4

Hos

pita

l Mor

talit

y

0 1 2 3 4 5 6Time to ABX, hours

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

Hospital Mortality by Time to ABX

Time to ABX1, hrs

OR2 95% CI p‐value

0 (ref) 1.00 ‐‐‐ ‐‐‐ ‐‐‐1 1.05 1.02 1.07 < 0.0012 1.09 1.04 1.15 < 0.0013 1.14 1.06 1.23 < 0.0014 1.19 1.08 1.32 < 0.0015 1.25 1.11 1.41 < 0.0016 1.31 1.13 1.51 < 0.001

Time to Treatment. Antibiotics

Ferrer et al. ESICM 2011, Abstract 139

25.089 patients with severe sepsis or septic shock

Predicted Mortality with 95% CI0

.1

.2

.3

.4H

ospi

tal M

orta

lity

0 1 2 3 4 5 6Time to ABX, hours

Severe sepsis Septic shock

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

Hospital Mortality by Time to ABX

Tratamiento antibiótico precoz y EGDT

En pacientes correctamente resucitados, el tiempo desde triage hasta el tratamiento antibiótico condiciona la mortalidad

Crit Care Med 2010; 38:1045–1053

Tratamiento Apropiado

Crit Care Med 2003;31:2742–2751

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: Treatments

PROTOCOL

GOAL

GOAL

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

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

Quantitative Resuscitation in sepsis:Meta analysis

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

Timing of Source Control

APACHE II Score

Relaparotomy< 48 hours

Relaparotomy> 48 hours

P

0 – 10 0 % 25 % 0.0911 – 15 0 % 33 % 0.0216 – 20 0 % 78 % 0.00221 – 25 57 % 100 % 0.02

> 26 79 % 94 % 0.2Total 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.

Early Treatment of Sepsis: Sepsis 6H Resuscitation Bundle

Source of infectionRisk factors for inadequate treatment

Local microbiological data

Adequate treatment

ABX Source Control EGDT

Early recognition of infection

Short Time to Treatment

Lactate Blood Cultures Radiology Central Line

Recognition of the Source of Infection

Lungs

Urinary Tract

Abdomen

Endovascular Catheters

Bilis

Skin and soft tissue

Meningitis

ICU

HOSPITAL

HEALTHCARE

COMMUNITY

Infection Setting, Resistances and Inadequacy of Treatment

RISK OF RESISTANCE

RISK OF INAPPROPRIATETREATMENT

Stratification: How do I recognize who is really sick with an infection?

Site of Care?

Renaud B et al. Clinical Infectious Diseases 2007; 44:41–9

CHEST 2010; 137(3):552–557

Early Recognition and Stratification

• Start treatment in early stages of sepsis.

• Reduce time to treatment. Sepsis golden hours.

• Reduce delayed source control techniques.

• Identify patients at high risk of death: adequate site of care.

Requires complete clinical evaluation + biomarkers

Estudio ABISS EdusepsisPrograma para la Administración Precoz del 

Antibiótico de Amplio Espectro en la Sepsis Grave

ABISS Edusepsis 2011

ABISS Edusepsis 2011

ABISS Edusepsis 2011

Resum

• Importància de l’atenció precoç.

• Reconeixement de la sèpsia:– Marcadors fisiològics. Avaluació Clínica.

– Biomarcadors

• Organització del tractament de la Sèpsia.

+ Infection

SIRS criteria at ICU admission

Outcome according SIRS criteria at ICU admission

87%

Crit Care Med 2009; 37:934 –938

Capillary refill time > 4.5s + Skin Cool to examiner’s hand

P< 0.05 P< 0.05

n= 50 ICU patients after resuscitation

Urinary output, arterial lactate level, cardiac index and SOFA score according to mottling

score at H6 after initial resuscitation

Kaplan-Meier survival estimates according to the H6 mottling score

Physiologic parameters associated with infection

Crit Care Med 2003; 31:2579 –2584

Am J Respir Crit Care Med Vol 171. pp 461–468, 2005

DEVELOPMENT OF THE RISSC FOR PROGRESSION FROM SEPSIS TO SEVERE SEPSIS OR SEPTIC SHOCK

BIVARIATE HR MULTIVARIATE HR

Am J Respir Crit Care Med Vol 171. pp 461–468, 2005

Progression from sepsis to severe sepsis or shock from day of diagnosis of infection

Crit Care Med 2003; 31:670 –675

Independent multivariate predictors of death in patients with infection

Crit Care Med 2007; 35:192–198)

Long time survival in patients with infection according MEDS

Physiologic Parameters and Sepsis

Infection in ICU1 Severe Sepsis orSeptic Shock in

infected2

Mortality in infected and in sepsis3

Tachycardia >80 or >140x´ >120x´ -Tachypnea - - >20x´ or SaO2<90%Fever > 37.5ºC >38.2ºC -Hypotension - SBP < 110mmHg Septic Shock

1. IPS. Peres Bota et al. Crit Care Med 2003; 31:2579 –25842. RISSC. Alberti C et al. Am J Respir Crit Care Med Vol 171. pp 461–468, 20053. MEDS. Shapiro N et al. Crit Care Med 2003; 31:670 –675

Variability of physiologic parameters

• ApEn is an statistical technique to measure regularity in time‐series analysis. 

• Physiological systems act like oscillators with high entropy.

Crit Care Med 2005; 33:512–519

LPS Administration

Crit Care Med 2005; 33:512–519

ApEn

Plos 1;2009

Heart rate variability in 21 bone marrow transplant patients

Am J Respir Crit Care Med Vol 174. pp 290–298, 2006

Independent predictors of mortality

Difference of complexitybetween survivors and nonsurvivors.

50 consecutive patients with MOF admitted to the ICU; TºC/10min

• survivedo died

Unspecific Approach

Triggering criteria: 10 signs of vitality

Crit Care Med 2007; 35:2568–2575

80% of shocks were detected50% were septic shockTimes to interventions and mortality decreased significantly over time

Resum

• Importància de l’atenció precoç.

• Reconeixement de la sèpsia:– Marcadors fisiològics.

– Biomarcadors

• Organització del tractament de la Sèpsia.

Biomarkers of Sepsis

Markers of :• Apoptosis

(e.g., caspase-3)

• Vasoregulation (e.g., BNP, proBNP, bigET-1, calcitonin)

• Organ and tissue dysfunction (e.g., NGAL, myoglobin, I-FABP, pulmonary surfactant proteins)

Markers of :• Pro-inflammation

(e.g., CRP, TNFα, IL-1β, IL-8)

• Anti-inflammation (e.g., IL-10, IL-6, soluble TNF receptors)

• Coagulation and fibrinolysis (e.g., D-dimer, tissue factor, protein C)

Time course: Endotoxin Challenge

Reinhardt K et. al. Crit Care Clin 22 2006 503-19

N Engl J Med 2004;350:451-8.

Independent predictors for diagnosing pneumonia

C‐Reactive Protein (CRP)

CRP measurement is a rapid, reproducible and inexpensive.

Acute Phase ProteinThe acute phase response accompanies inflammation. 

Acute phase proteins are defined as those proteins whose plasma concentrations increase by at least 25 percent during inflammatory states 

Changes in levels of acute phase proteins result from cytokines: IL‐6, IL‐8 effect on hepatocytes

• In sepsis and inflammation• Proinflammatory

mediators (IL-1ß, TNFa, LPS) induce CT-mRNA

• Unprocessed PCT is released

• Classical neuroendocrine paradigm• Expression of CT-mRNA

is restricted to neuroendocrine cells (C-cells of the thyroid)

• PCT is processed to CalcitoninLinscheid P et al., Endocrinology, 2003

Procalcitonin: a ‘hormokine’

Procalcitonin as a diagnostic test for sepsis: A systematic review and meta-analysis.

Global diagnostic OR for PCT2966 pts25 studies15.7 (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 CRP1322 Pts15 studies5.4 (3.2-9.2)

Uzzan et al. Crit Care Med 2006; 34:1996–2003

Q* PCT 0.78 vs. Q* CRP 0.71 p = .02

Accuracy of Procalcitonin for Sepsis Diagnosis in Critically Ill Patients:

Systemic Review and Meta-Analysis

Tang BM et al Lancet Infect Dis 2007;7:210-17

Sensitivity and specificity: 71%(95% CI 67–76)AUC 0·78 (95% CI 0·73–0·83).

Crit Care Med 2009;37:96-104

• Design: Prospective multicenter observational study.• Patients: 971 patients septic enrolled.• Nine biomarkers were assayed.• Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. • Derived formula for weighting biomarker values was used to calculate a “sepsis score”

Crit Care Med 2009;37:96-104

BIOMARKER PANEL IN SEVERE SEPSIS

Probability of severe sepsis:

Shapiro N et al. Crit Care Med 2009;37:96‐104

BIOMARKER PANEL IN SEVERE SEPSIS

Dynamic measurements: infection prediction

Castelli et al.  Crit Care Med 2009

INFECT

ION

Lobo SM, Lobo FR, Bota DP et al. Chest. 2003;123:2043-9.

CRP Levels Correlate With Mortality and Organ Failure in Sepsis

30

20

10

0

30

20

10

0

*

* p < 0.05

Number of Organ Failures

0 1 2 3 > 4(116/115) (111/110) (56/56) (20/19) (4/4)

Day 0 Day 2

CR

P m

g/dL

CR

P m

g/dL

CRP Day 0CRP Day 2 Survivors

Non Survivors

p = 0.002p = 0.001

Survivors vs. Non-Survivors

Differentiation between Sepsis and SIRS

S. Harbarth et al. Am J Respir Crit Care Med 2001;164:396-402

Plasma levels of PCT, IL-6 y IL-8

Medical and surgical ICU pat. (n=78),with SIRS and suspicion of infection

Lactic Acidosis

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

Glycogen

Glucose Pyruvate

Lactate

CitricAcidCycle

CO2H2O

(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

38-40%

28 day in-hospital mortality Death within 3 days

Lactate1

30

25

20

15

10

5

00-2.4 2.5-3.9 > 4.0

% o

f Mor

talit

y R

ate

% o

f Mor

talit

y R

ate

0-2.4 2.5-3.9 > 4.0N = 827 N = 238 N = 112

Initial Lactate (mmol/L)2

50

40

30

20

10.0

0.0

Serum Lactate as a Predictor of Mortality

1 Trzeciak S, Dellinger RP, Chansky ME et al. Intensive Care Med. 2007;33:970-7.2 Shapiro NI, Howell MD, Talmor D et al. Ann Emerg Med. 2005; 45:524-8.

28%

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

ShockNon-Shock

28-D

ay M

orta

lity

(%)

50454035302520151050

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

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

Time

Lact

ate

(mm

ol/L

)

Survivors

Non-survivorsp < 0.05p < 0.05

p < 0.01

Lancet 2010; 375: 463–74

Lancet 2010; 375: 463–74

Patients receiving antibiotics for days 1–28 Mortality

Jensen J et al. Crit Care Med 2011; 39:2048 –2058

A strategy with escalation of broadspectrum antimicrobials guided by daily procalcitonin measurements

Jensen J et al. Crit Care Med 2011; 39:2048 –2058

P< 0.004

Resum

• Importància de l’atenció precoç.

• Reconeixement de la sèpsia:– Marcadors fisiològics.

– Biomarcadors

• Organització del tractament de la Sèpsia.

Time‐dependent Diseases

• Acute Myocardial Infarction

• Stroke

• Trauma/Hemorrhagic shock

• Severe Sepsis

“The Golden Hour”

Time‐dependent Diseases

AMI STROKE TRAUMA SEPSISClinical Recognition Easy Easy Easy Complex

Population Homogeneous Homogeneous Heterogeneous HeterogeneousBiomarker YES NO NO YES/NOComplex TreatmentAlgorithms

++ ++ +++ +++

Multidisciplinary Approach + ++ +++ +++

Well established guidelines

+++ +++ +++ ++

Code Yes Yes Yes +/-

Sepsis Treatment

Annane D et al. Lancet 2005; 365: 63–78

Severe Sepsis Scenario

In Sepsis, Speed is Life

Sepsis Resuscitation Bundle

EDUCATIONALPROGRAMME

POST-EDUCATIONDATA COLLECTION

OCT-DEC JAN-FEB MAR-JUN

2005 2006

BASELINE DATA COLLECTION

a before-and-after intervention study

2007

LONG-TERMFOLLOW-UP

MAR-JUN

JAMA 2008;299(19):2294-2303

Study Timeline

PER

CEP

TIO

N

Resuscitation Bundle (6H)

0

10

20

30

40

50

60

70

80

90

% C

ompl

ianc

e

Lactate Blood Cultures Antibiotics Fluids +Vasopresors

CVP>8 SvcO2>70 All

Preintervention Intervention

* p<0.05

*

*

*

*

* *

Educational Program and Mortality

4439,7

36,431,1

0

10

20

30

40

50

%

Hospital Mortality ICU Mortality

Preintervention Intervention

p= .036 p= .01

Absolute reduction: 4.3%Relative reduction 10%

28d Mortality: Kaplan-Meier curve

Absolute reduction: 4.3%Relative reduction 10%SSC objective was 25%!

Crit Care Med 2010;38(2):668-678

Crit Care Med 2010;38(2):668-678

How to Go Fast

EVENT DETECTION(Bedside nurses and clinicians)

INITIAL TREATMENT(Bedside nurses and clinicians)

SPECIALIZED TREATMENT(RRT, MET or ICU)

Sepsis Rapid Response System

Crit Care Med 2011; 39:252–258

The sepsis response team members

Elements of the sepsis resuscitation bundle

Compliance with sepsis bundles

Independent predictors of

mortality

Crit Care Med 2011; 39:252–258

Deliver of Bundled Care

• Sepsis code

• Rapid response teams

• Audit

• Quality improvement interventions

Kumar A et al. Current Opinion in Critical Care 2009, 15:301–307

Ovoid delays in treatment

Antibiotic Prescription

Transmit Medical Order

Antibiotic Administration

Help for Prescription

Specific Pathway for Emergent Treatments

Stock of Pre-dilutedBroad Spectrum Antibiotics

Standardized Hospital Order Set

Crit Care Med 2009; 37:819–824

Standardized Hospital Order Set

Crit Care Med 2009; 37:819–824

Take Home Messages

Sepsis is time dependent: TEMPUS FUGIT

Take Home Messages

Early Recognition based on:• Careful Clinical Examination• Biomarkers

Take Home Messages

Early Treatment based on:• Microbiological information.• Infection Setting and local resistance pattern.

• Source of infection• Biomarkers 

Take Home Messages

Early Transfer to the adequate site of care

• Bundled care reduce mortality in severe sepsis.

• Programs of knowledge translation based on bundles reduce mortality and are efficient.

Hospitals should adapt their organization to this evidence!

Take Home Messages

Ricard FerrerCritical Care Department

Mutua Terrassa University HospitalBarcelona. SPAIN