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UWE Bristol
Sepsis in the Intensive Care
Name Diane Standring
TitleSenior lecturer critical care
Learning outcomes
To revise the pathophysiology of sepsisTo consider key elements of
the sepsis bundleTo relate elements to pathophysiologyTo Consider
evidence behind recommendations
Definitions
Sepsis : defined as infection plus systemic manifestations of
infectionSevere sepsis: sepsis plus sepsis induced organ
dysfunction or hypoperfusionSchulman (2003) describes the
phenomenon as the unifier of critical care
Incidence
Associated with a mortality of 82% (Cuneen & Cartwright 2004).
Incidence is increasing and likely to continue (Dellinger et al
2008)27% of patients admitted UK ITU (n92) met severe sepsis
criteria within 24 hours of admission and accounted for 40% of the
ITU budget (Bray 2006). Risk of sepsis increases with age (Desbiens
2006) & pre-existing co-morbidity
A non-specific clinical response including >2 of the following:
As well as infection, SIRS can also be caused by trauma, burns,
pancreatitis and other insults
The disease continuum
Sepsis
SIRS
Infection
Severe sepsis
Death
Temperature >38oC or 90 beats/minRespiratory rate
>20/minWhite blood cell count >12,000/mm3 or 10% immature
neutrophils
The disease continuum
Sepsis
SIRS
Infection
Severe sepsis
Death
SIRS with a presumed or confirmed infectious process
The disease continuum
Sepsis
SIRS
Infection
Severe sepsis
Death
Sepsis with signs of at least one acute organ dysfunction
RenalRespiratoryHepaticHaematologicalCentral nervous
systemUnexplained metabolic acidosisCardiovascular
Septic shock Severe sepsis with hypotension refractory to adequate
volume resuscitation
Pathogens involved in sepsisAn overview
Only 60% of severe sepsis/septic shock cases are associated with
confirmed infection WHY ?
Gram negative
Gram positive
Fungal infection
Mixed bacterial
Other mixed
Unconfirmed
20%
19%
10%
45%
3%
3%
Bacterial pathogens in sepsisA final common pathway?
Gram-negative
Gram-positive
Cell wall componentsExtracellular products
Endotoxin and other toxins
SEPSIS
INFLAMMATION
e.g. Staphylococcus aureusStreptococcus pneumoniaeEnterococcus
faecalis
e.g. Neisseria meningitidis Escherichia coli
Host immune response
Host immune response
Host response to infection
Homeostasis
Fibrinolysis
InflammationCoagulation
Pathogenesis of sepsis
In sepsis
Fibrinolysis
Endothelial dysfunction
InflammationCoagulation
Loss of homeostasis
Inflammatory response to microbial toxins
GM-CSF: granulocyte macrophage colony-stimulating factor
white blood cell adhesion to endothelium
IL: interleukin
White blood cell adhesion
ICAM: intercellular adhesion molecule, TNF: tumour necrosis factor,
IL: interleukin
Rolling
Selectins
Direct signalling
Chemokines
Activation of integrins
ICAM-1
Receptors
TNF, IL-1
Loss of inflammatory control in sepsis
Hypo-responsiveOverwhelming sepsisExcess
compensation/CARSImmunosuppressionIncreased susceptibility to
secondary infection
Balanced response
Hyper-responsiveSepsis, severe sepsis and MODS
Resolution
Death
Death
INFLAMMATORY RESPONSE
Anti-inflammatory/pro-inflammatory mediators and
cytokines
Endothelial dysfunction in sepsis
Interaction with leucocytesRelease of cytokines and inflammatory
mediatorsRelease of mediators of vasodilatation and
vasoconstrictionFunctional effects on the coagulation system
The role of the endothelium
Tissue injury
Formation of fibrin clot
coagulation and fibrinolysis
Thrombin
Reduced fibrinolysis in sepsis
TAFI: tissue activatable fibrinolysis inhibitor, PAI-1: plasminogen
activation inhibitor-1,
Reduced fibrinolysis
Microthrombi remain
Pro-coagulant mechanism
Thrombin
TAFI
Endothelial dysfunction
TNF-, IL-1
PAI-1
Coagulation pathways
Common pathway
Extrinsic pathway
Intrinsic pathway
VII
VIIa
Tissue factor
IX
IXa
XIa
XI
XIIa KallikreinHMW kininogen
+
+
+
X
Xa
Prothrombin
Thrombin
Fibrinogen
Fibrin
Cross-linked fibrin
V Ca2+
+
+
VIII
XIIIa
+
+
Fibrinopeptides A+B
CLOT FORMATION
3.12
HMW kininogen: high molecular weight kininogen
Other factors involved in the host
Energy disruption in sepsis: mitochondrial dysfunction
TCA: tricarboxylic acid, ADP: adenosine diphosphate, ATP: adenosine
triphosphate
Mitochondrial dysfunction in sepsis
Organs may sometimes fail despite adequate perfusion with
oxygenated bloodOxygen utilization at a cellular level may be
impaired in sepsis dysoxia Mitochondrial inhibition is likely to
have a role in organ dysfunctionLevels of pro-inflammatory
cytokines, nitric oxide and other reactive species can inhibit
mitochondrial function
Protein C
Endogenous protein C is a vitamin K-dependent protein produced in
the liver.
The activation of endogenous protein C takes place on the endothelium; endogenous protein C is cleaved in the presence of calcium ions to form endogenous activated protein C.
In sepsis, damage to vascular endothelium diminishes the bodys ability to convert endogenous protein C to endogenous activated protein C.
Take a deep breath !
protein C in sepsis (??)
Tissue injury
Organ failure/shock
Death
Activated protein C
Coagulopathy
Suppressed fibrinolysis
Thrombin generation
TAFI activated
Endogenous protein C
Infection
Tissue factor expression
Activated coagulation
Endothelial injury
Leucocyte activation
Activated inflammation
Increased PAI-1
Pro-inflammatory mediators
Microvascular endothelial dysfunction
Inactivation
PAI-1: plasminogen activation inhibitor 1 TAFI: tissue activatable
fibrinolysis inhibitor
Surviving sepsis campaign 2001,2003,2006,2007(Dellinger et al
2008)
11 international critical care
organisationsMultidisciplinarySystematic review of literature25%
reduction in sepsis mortality by 2007 (!)Sepsis resuscitation
bundleSepsis Management bundle
Improving outcomes
Early aggressive fluid managementEarly start antibioticsEarly
ethical decision makingEarly use of central lineEarly use of
central blood gas analysis (lactate)Early involvement of
ITU
Sepsis resuscitation bundle
Measure serum lactateBlood cultures prior to Antibiotic
TxAdminister broad spectrum antibiotics within 3 hours of ED
admission or 1 hour of non ED admissionIf hypotensive or lactate
>4.0mmol/LGive 20ml/kg crystalloidVasopressors to maintain MAP
.65mmHgPersistant hypotension and lactate > 4.0mmol/lCVP >8
mmHgSv02 .65%
Sepsis management bundle
Antibiotic therapySource identification and controlFluid
therapyVasopressorsInotropic therapySteroidsActivated protein
CBlood products
Sepsis management bundle cont.
Mechanical VentilationSedation analgesia and neuromuscular
blockadeGlucose controlRenal replacementBicarbonate therapyDVT
prophylaxisStress ulcer prophylaxisConsider limitation of
support
Group work
In groups of 7 (X 6 groups)Consider the aspect of the sepsis bundle
you have been given.Explore the research / evidence baseContribute
from your own experience ? Use of guideline, protocol ? theory
practice gap Prepare to feedback to whole group
Things to consider
How does this management issue relate to pathophysiology of
sepsisIs the research conclusive or conflictingWhat is the evidence
base used by the surviving sepsis campain
30 minutes
Topics
Fluid therapy and blood productsVasopressors and
inotropesSteroidsActivated protein CMechanical ventilationGlucose
control
Sepsis management bundle
Antibiotic therapyBoard spectum within 1 hourDo not wait for
culture results
Sepsis management bundle
Source identification and controlEarly surgical intervention except
pancreatic necrosisConsider re citing invasive lines
Sepsis management bundle (a)
Fluid therapyCrystalloid Vs CollidCVP > 8 in self ventilating
patients > 12 in vented300-500 ml challenges over 30 minsBeware
cardiac filling pressures increasing without concurrent rise in
BP
Sepsis management bundle (a)
VasopressorsMAP >65mmHgNoradrenaline or dopamineAdrenaline if
poor responseNo renal dopamine !
Sepsis management bundle (a)
Inotropic therapyDobutamine for myocardial dysfunctionDo not drive
cardiac index to supranormal
Sepsis management bundle (a)
SteroidsConsider hydrocortisone when hypotension poorly responsive
to fluid challengesACTH testing not recomendedSteroids maybe weaned
once vasopressors offDo not use in the absence of shock
Sepsis management bundle (a)
Activated protein CConsider if sepsis induced organ dysfunction and
high risk of death (APACHE > 25)Do not use with single organ
failure or APACHE
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