Ch.2 Systemic Inflammatory Response Flashcards
What is SIRS
An incongruous and exaggerated systemic inflammatory reaction as response to infection and injury
What is CARS
Compensatory Anti-inflammatory Response Syndrome
Over recruitment of the anti-inflammatory processes
A state of anergy, increased susceptibility to infection and inability to repair damaged tissues.
What occurs in MARS - Mixed anti-inflammatory response syndrome
Surges of both CARS and SIRS coexist
What is the key event in the initiation and propagation of SIRS
Release of endogenous molecular substances by the hosts innate immune system
What are PAMPs
Pathogen associated molecular patterns - products released or associated with invading microorganisms
What are DAMPs
Damage associated molecule pattern - Products released from damaged cells
Function of PRRs (pattern recognition receptors)
Recognise PAMPs and DAMPs and initiate downstream release of endogenous mediators that drive the inflammatory response.
Proinflammatory cytokine examples
TNF - Tumour necrosis factor
Interleukin 1 IL-1
Interleukin 6 IL-6
Interleukin 8 IL-8
IFN-y - Interferon-y
Universal sources for proinflammatory cytokines
Macrophages and monocytes
Other cell types contributing
Neutrophils - TNF
Endothelial cells - IL-1, IL-8
Fibroblasts
Keratinocytes
Lymphocytes - IL-1, IL-6
Natural Killer Cells - TNF, IFN-y
Main functions of TNF, IL-1 and IL-6
Initiate coagulation,
Fibrinolysis,
Complement activation,
Acute phase response,
Neutrophil chemotaxis
TNF&IL-1 - Pyrogenic activities, augment further cytokine production
What is phospholipase A2 responsible for?
Cleavage of arachidonic acid
What up regulates phospholipase A2
IL-1, TNF, Endotoxin
What is arachidonic acid metabolised by and what are the metabolites
Lipoxygenase - Leukotrienes
Cyclooxygenase - Prostanoids ; Thromboxane A2(TxA2) and Prostaglandins (Pgs)
Which prostanoids are vasoconstrictors?
TxA2 (Thromboxane A2)
PGF2Alpha
Which prostanoids are vasodilators?
PGI2
PGE2
Role of prostanoids in primary homeostasis
TxA2 - promotes platelet aggregation
PGI2 - inhibits platelet aggregation
Which prostanoid is a pyrogen
PGE2
Action of leukotrienes in horses
Chemoattractants and increase vascular permeability
Where does PAF (Platelet Activating Factor) come from?
Released from cell membrane by phospholipase A2
Biologic effects of PAF?
1 - Vasodilation
2 - Increased vascular permeability
3 - Platelet aggregation
4 - Recruitment and activation of phagocytes
What is the expected SAA conc in healthy horses and foals?
<27mg/L
What test is used to determine SAA levels
Latex agglutination immunoturbidimetric assay
What test is used to determine C-Reactive protein (CRP)
Radial immunodiffusion
What is the expected CRP conc in healthy horses and foals?
5-14mg/mL
The compliment system is represented by the acute phase synthesis of
C3a C3b
C4a C4b
C5a C5b-C9
Factor B
C1 inhibitor
What do the compounds of the complement system do?
1- Induce bacteriolysis
2 - Increase vascular permeability
3 - Chemotaxis for neutrophils
4 - Enhance opsonisation for microbes and damaged host cells
Reactive oxygen species encompass all oxygen-derived toxic mediators that originate from what
Mononuclear phagocytes or neutrophils
The rxns and re-pairing of free radicals causes what to occur
1 - Molecular damage
2 - Loss of protein function
3 - Cross-linking of DNA
4 - Lipid per oxidation
5 - Vasoconstriction
6 - Pain
Oxygen free radicals also:
7 - Cytokine production
8 - Endothelial adhesion models
SIRS criteria in horse
Temp >38.5 (101.3) or <37 (98.6)
HR >52
Resp >20 or PaCO2<32mmHg
WBC >12,500 cells/uL or <5000 cells/uL or >10% bands
Cut off value for Lactate (SIRS criteria)
2.06mmol/L
In the Sepsis score system for neonatal foals; a nn. foal
from a mare with hx of placentitis, valvular dc, dystocia, Long transport of mare, sick mare, induced parturition, prolonged gestation >365 days will score where on the scale
3
A nn. foal born at 300-310 days of gestation will have a sepsis score of?
2
A nn. foal born under 300 days will have a sepsis score of?
3
A nn. foal with a temp of >39*C will have a sepsis score of
2
NN. Foals with anterior uveitis, diarrhoea, respiratory distress, swollen joints, open wounds earns a sepsis score of
3
What neutrophil count scores a sepsis score of 3 in a nn. foal
<2,000/uL
What neutrophil count scores a sepsis score of 2 in a nn. foal
2,000-4,000/uL or >12,000/uL
What neutrophil count scores a sepsis score of 1 in a nn. foal
8,000-12,000/uL
How many bands per uL scores a 3 and a 2 in nn. foal sepsis score
3 - >200
2 - 50-200
What is necessary for a nn. foal to score 4 on the nn foal sepsis score
Marked toxic change in neutrophils
IgG <200mg/dL
A score of what predicts sepsis in a nn. foal according to the sepsis scoring system
> 11
What is MODS
Multiple organ disfunction syndrome
Presence of altered organ function in an acutely ill patient such that hemostasis cannot be maintained without intervention.
A dynamic process that is a continuum of pathophysiologic change over time.
An extension and possible consequence of SIRS
Describe primary MODS
Any disease process inducing a well-defined injury that affects the function of organs at the initial site of insult
Describe secondary MODS
Any disease process inducing a well-defined injury that affects the function of organs remotely positioned from the primary injury, not as a direct response to the insult but as a consequence of the host’s response to the injury.
What are the pathophysiological events that drive MODS
1 - Immune mediated inflammatory injury
2 - Altered hemodynamics
3 - Dysfunction of the autonomic nervous system
4 - Reduced tissue perfusion
The major elements that define dysfunction of the coagulation system associated with the development of MODS are?
1- Excessive pro coagulation
2 - Loss of controlled fibrinolysis
3 - Loss of natural anticoagulant activities
What occurs in DIC
prolonged or excessive thrombi formation results in platelets, coagulation factors, anticoagulant factors and fibrinolytic factors being consumed - balance is lost and haemorrhage may ensue
What % of horses with acute colitis fit the diagnostic criteria for DIC at admission
30%
What % of horses with large colon volvulus fit the diagnostic criteria for DIC at admission
70%
What % of septic foals fit the diagnostic criteria for DIC at admission
25%
What is the primary mechanism for the initial hypercoagulative state of DIC
Activation of the extrinsic coagulation cascade via enhanced expression of membrane tissue factors
In horses endotoxin favours activation of which tPA or PAI?
PAI (Plasminogen activator inhibitor)
Consequences of low Protein C and AT
Increased clot formation and heightened inflammatory response - resulting in further thrombus formation
Which horses are likely to have increased y-glutamyltransferase activity? Small strangulating lesions or proximal enteritis
Proximal enteritis - 12 times more likely
Acute renal failure is described as what
The presence of azotemia or oliguria or both in a normovolemic patient that does not have signs of post renal obstruction
What is the primary mechanism leading to acute renal failure
Acute tubular necrosis
Acute lung injury (ALI) and (ARDS) Acute respiratory distress syndrome are defined as the clinical conditions of acute respiratory failure, what are they characterised by?
Hypoxemia
Diffuse bilateral pulmonary infiltrates on thoracic radiographs in the absence of left atrial hypertension
When do ALI and ARDS develop
When injury to the alveoli and pulmonary endothelium cause thromboembolism and protein rich pulmonary oedema
Type II pneumocytes and fibroblasts are recruited to replace damaged areas in the aleveoli
Triggers for ALI and ARDS in horses are
Sepsis
Aspiration of GI content
Smoke
Severe trauma
Transfusion run
What is the term CIRCI, Critical illness related corticosteroid insufficiency used to describe
Cortisol response is insufficient for the degree of stress induced by the illness
ALR and ADRS can be suspected in horses that meet what criteria
1 - Acute onset <72hrs of respiratory distress or tachypnea at rest
2 - Patient has a known risk factor
3 - Pulmonary capillary leakage w/o increased pulmonary capillary pressure
4 - There is inefficient gas exchange
DIC can be suspected in the presence of
1 - Thrombocytopenia
2 - Prolonged prothrombin; activated prothrombin time
3 - Decreased fibrinogen concentration or prolonged thrombin time
4 - Increased fibrin degradation products or D-dimer concentrations
5 - Decreased antithrombin activity
What are the most commonly recognised clinical abnormalities of the coagulation system in horses with acute GI disease?
Thrombocytopenia
Prolongation of the prothrombin time
What is the mean urine production in foals?
6ml/kg/hr
Liver specific indices in the horse?
Persistently increased:
serum sorbitol dehydrogenase
y-glutamyltransferase
serum bile acid conc
What is normal fraction shortening for most light breed adult horses?
28-45%
Define septicemia
Microbial invasion into the bloodstream with a concurrent systemic host response.
In what % of horses with acute colitis does bacteremia occur in?
29%
What do PRRs (Pattern recognition receptors) do?
Detect microbial ligands called PAMPs - pathogen associated molecular patterns
What are PAMPs?
Ligands unique to microbes - usually essential for microbial survival or virulence. Eg - bacterial cell wall extracts
Examples of PAMPs
Bacterial cell wall extracts such as
endotoxin,
peptidoglycan
lipoteichoic acid
prokaryotic DNA
What are the 3 types of PRRs
1- Defensins (Secreted)
2 - Cell membrane PRRs (involved in phagocytosis)
3 - Cell membrane PRRs (signal transduction)
Example of a well-characterised cell signalling PRR-ligand relationship
CD14-Toll like receptor (TLR) and its PAMP Endotoxin
Characteristics of endotoxin
Heat stable
G-
Lipopolysaccharide = 75% of outer cell membrane
What are the 3 structural domains of endotoxin?
- Core - Monosaccharides
- Core - Lipid A (Highly toxic)
- Outer - polysaccharide “O-Antigenic” region
How does endotoxin manifest its pathologic effects
Once in the blood forms aggregates resembling micelles
What is an LBP Lipopolysaccharide binding protein and what does it do?
Lipid transfer protein synthesised by the liver
Acute phase protein
Extracts molecules of endotoxin from aggregated micelles in the blood and transports them to various locations.
What is CD14
53-kDa Glycoprotein exists as a cell membrane receptor(mCD14) and a soluble form in circulation(sCD14)
sCD14 - Binds and neutralises circulating endotoxins
Does not structurally cross the cell membrane so associates with TLR
What is the most important TLR in the recognition of endotoxin?
TLR4
What does TLR2 recognise?
Gram positive bacteria
What is thought to be responsible for some violent runs to endotoxin?
Polymorphism of TLR4
What is the easy hyper dynamic phase of endotoxemia characterised by
Pulmonary hypertension and ileus associated with increased levels of Thromboxane A2
What is the easy hypodynamic phase of endotoxemia characterised by
Fever and hypotension
Decreased systemic vascular resistance due to PG release
What is the gold standard test for Endotoxemia
The LAL - Limulus Amebocyte Lysate assay
But not clinically practical
What is the cardinal diagnostic marker for endotoxemia?
Profound neutropenia with toxic neutrophil morphology with a left shift
How long after the onset of endotoxemia will neutropenia occur
1 hour
Dose of smectite orally for endotoxemia
4 ounces orally twice daily
The effectiveness of Antiendotoxin antibodies and Polymyxin B is a factor of what
Their dose and the amount of free unbound circulating endotoxin
What is Endoserum and how is it used?
Hyperimmune serum from horses vaccinated with the Salmonella typhimurium Re mutant
It is diluted with sterile isotonic saline 1:10 or 1:20 and administered iv over 1-2 hours
What is Polymyxin B
A cationic antibiotic which also binds to and neutralises endotoxin through direct molecular interactions with the lipid A region.
Cons of Polymyxin B
Nephrotoxic
Neurotoxic when used at bactericidal doses
Recommended dose of Polymyxin B
1000-6000 IU/Kg BWT IV every 8-12 hours
Doses of DMSO used for endotoxemia
0.1-1g/kg bw diluted to 10% in isotonic fluids
Flunixin in endotoxemia tx
Prevents endotoxin induced Prostanoid synthesis
