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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.
1. INTRODUCCIÓN MEDICINA INTENSIVA
Cada 4 segundos
alguien muere por sepsis en el
mundo
1. INTRODUCCIÓN MEDICINA INTENSIVA
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
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%
Pillars of Sepsis Treatment
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
Pillars of Sepsis Treatment
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
Pillars of Sepsis Treatment
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.
Ricard Ferrer
Intensive Care Department
Mutua Terrassa University Hospital
Barcelona. SPAIN