Académique Documents
Professionnel Documents
Culture Documents
Proinflammation Antiinflammation
TNF- Thromboxane IL-1 ra
IL-1, IL-1 Platelet activating factor IL-4, IL-6
IL-2 Soluble adhesion IL-10, IL-11
IL-6 molecules IL-13
IL-8 Vasoactive neuropeptides Type II IL-1 receptor
IL-15 Phospholipase A2 TGF-
IFN- Tyrosin kinase Epinephrine
Neutrophil elastase PAI-1 Soluble TNF- receptors
Protein kinase Free radical generation Leukotriene 4-rec.
MCP-1 & 2 Neopterin antagonism
Leukemia inhibitory CD 14 Soluble recombinant CD 14
factor Prostacyclin, Prostaglandin LPS binding protein (LBP)
Pathophysiology of Severe Sepsis
Endothelium COAGULATION
CASCADE
Tissue Factor
Factor VIIIa
PAI-1
IL-6
IL-1
Organisms TNF-
Monocyte
Factor Va
Suppressed
fibrinolysis
THROMBIN TAFI
Neutrophil
Fibrin
IL-6
Fibrin clot
Tissue Factor
1. General variables
2. Inflammatory variables
3. Hemodynamic variables
4. Organ dysfunction
5. Tissue perfusion
General Fever or hypothermia (temperature > 38.3C or < 36C
variables Heart rate > 90 bpm or > 2 SD above the normal value for age
Tachypnea, altered mental state
Significance edema or positive fluid balance (> 20 ml/kg over 24 h)
Hyperglycemia (PG > 120 mg/dl or > 7.7 mmol/l) while diabetes absents
Hemodynamic Arterial hypotension (SBP < 90 mmHg, MAP < 70 mmHg, or SBP
variables decrease > 40 mmHg in adults or < 2 SD below normal for age
SvO2 > 70%
Cardiac index > 3.5 l/min x M-2
Shock
Respiratory
Hepatic
Hematologic
CNS
Metabolic acidosis
Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.
MANAGEMENT
Management of Sepsis
Diagnosis Therapy
Supportive
Lab routine
lnitial resuscitation Specific
Culture
Fluid therapy
Antimicrobials
Radiologic exam
Steroids
APC
Biochemical
Vasopressors/inotropic
markers: LBP, PCT, Source control
CRP, IL Mechanical ventilation
Modification of
Blood tranfusion inflammation
Dialysis, glucose
control
Identification of High-Risk Severe Sepsis
SPECIFIC
THERAPY
MANAGEMENT
Based on Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock
Supportive therapy
initial resuscitation, fluid administration, vasopressors and
inotropic agents, steroids, blood transfusion, mechanical
ventilation, glucose control, dialysis, prevention of DVT and
stress ulcer, bicarbonate, and renal replacement
Specific therapy
antimicrobial agents, activated protein C, source control, and
modification of inflammatory response
Initial Resuscitation (early goal directed therapy)
Factors XII
Complement
LPS-binding ENDOTOXIN
protein CNS CRF
Stress
TNF- IL-1 hormones
Lypoxygenase PAF Cyclooxygenase
(leukotriens) (prostanoids)
Nitric
oxide Mandell G, 2002; Essential Atlas
of Infectious Diseases
Gram
negative
PMN
bacteria
Liver
Lipopolysaccharide
(LPS)
BACTERICIDAL
Permeability-increasing
protein (BPI)
LPS-binding
protein (LBP)
LPS/BPI LPS/LBP
Complex Complex
CD14
LPS G
degradation protein
Kinase activation
NF kB
Nuclear translocation
Macrophage
Increased transcription
CD14
Macrophage
TNF, IL-1, IL-6, IL-8,
pletelet-activating factor
ARDS
Endothelial damage
MOF
ANTIBIOTIC SELECTION BASE ON
Antimicrobial dosing
infection
endotoxin & other microbial toxins
proinflammatory state with cytokine release and
other proinflammatory mediators
sepsis / SIRS
shock & MODS & possible death
SEPSIS, SIRS, CARS, MARS (Bone, 1997)
Local Local
proinflammatory antiinflammatory
response Initial insult (bacterial, viral, response
traumatic, thermal)
4. Excessive immunosuppression
5. Immunologic dissonance
Not beneficial
Anti TNF (dose dependent increase in 28 day mortality)
Insulin 33 71*
(median units/day)
Duration of Insulin 67 100*
use (% ICU days)
AM glucose 153 103*
(all patients)
AM glucose 173 103*
(Insulin patients)