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
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