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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