Chapter 2 - SIRS Flashcards
systemic inflammatory response and failure of multiple organ systems are a
syndrome
What is the Systemic Inflammatory Response?
inappropriate and generalized inflammatory response to stimuli, which may or may not result from an infectious process.
The key event in the initiation and propagation of SIRS is the release of
endogenous molecular substances (Bacteria or their endotoxins, or both)
What is the ultimate goal of the immune system in microbial invasion or tissue damage?
To contain infection, alarm the host, and promote tissue repair
What can initiate Systemic Inflammatory Response Syndrome (SIRS)?
Infection, endotoxemia, severe trauma, ischemia, or hypoxemia
What is the Compensatory Antiinflammatory Response Syndrome (CARS)?
Over-recruitment of antiinflammatory processes leading to anergy
What are cytokines in the context of SIRS?
Protein substances that respond to infectious agents or tissue damage
what are the 2 types of cytokine?
proinfalmamtory: tumor necrosis factor (TNF); interleukin 1, 6, and 8 (IL -1, IL -6, and IL -8, respectively); and interferon-γ (IFN-γ)
antiinflammatory ILa4, IL-10, Il-11, IL-13, TGF-β
who produces the proinflammatory cytokines TNF, IL and IFN-γ?
Monocytes and macrophages, neutrophils (TNF), fibroblasts, keratinocytes, lymphocytes (IL-1, IL-6) and natural killer cells (TNF, IFN-γ) endothelial ç are universal sources for the proinflammatory cytokines,
what are the main functions of TNF, IL-1 and IL-6?
initiate coagulation, fibrinolysis, complement activation, the acute phase response, and neutrophil chemotaxis. TNF and IL -1 also induce** pyrogenic** activities
What type of molecule is arachidonic acid
Arachidonic acid is a 20-carbon fatty acid that is a major constituent of the phospholipids of all cell membranes
What is the role of arachidonic acid in SIRS?
To be a precursor for eicosanoid synthesis
In experimental horses infusion of endotoxin results in
increased circulating levels of TNF and IL -6
in septic foals that did not survive, IL -___ gene expression was significantly greater than in surviving ones
in septic foals that did not survive, IL -10 gene expression was significantly greater than in surviving ones
Endotoxin, TNF, and ILil-1 all upregulate the activity of
phospholipase A2, the enzyme responsible for cleavage of arachidonic acid
Once released, arachidonic acid is further metabolized by either ________________ to form the family of leukotrienes, or __________________, to form the prostanoids: thromboxane A2 (TxA2) and the prostaglandins (PGs).
Once released, arachidonic acid is further metabolized by either lipoxygenase to form the family of leukotrienes, or cyclooxygenase, to form the prostanoids: thromboxane A2 (TxA2) and the prostaglandins (PGs).
The prostanoids are vasoactive substances: TxA2 and PGF2α are potent
The prostanoids are vasoactive substances: TxA2 and PGF2α are potent vasoconstrictors
The prostanoids PGI 2 and PGE2 are
PGI 2 and PGE2 are vasodilators
PGE2 has 2 functions name them
vasodilation and pyrogen
What is the key initiation and propagation of SIRS?
invading microorganism release PAMPs or DAMPs
what does it mean PAMPS and DAMPs
pathogen-associated molecular patterns [PAMPs])
damage-associated molecular patterns [DAMPs]
who recognize the PAMPs and DAMPs and releases endogenous mediators that drive inflammatory response?
Host cell–associated pattern recognition receptors (PRR s)
What is the name of multiple organ dysfunction syndrome?
MODS
Platelet - Activating Factor is released from cell membrane of which ç?
mononuclear phagocytes
endothelial ç
platelets
phospholips by phosphilipase A2
The released **alkyl-lyso-glycerophosphocholine **is then acetylated to form PAF. The biologic effects of PAF include
vasodilation,
increased vascular permeability,
platelet aggregation,
and recruitment
and activation of phagocytes
What does it mean to be acute phase protein?
An acute phase protein is any protein whose blood concentration significantly increases (or decreases) during an inflammatory response
What happens when SIRS and CARS are appropriately balanced?
Homeostasis resumes in the host
What is believed to be responsible for the development of clinical signs and symptoms in systemic inflammatory response?
The phagocytic activation of the monocyte/macrophage cell lineage is thought to be directly responsible.
What is the general accepted summary of conditions leading to systemic inflammatory response?
It’s generally accepted that bacteria or their endotoxins, or both, induce and sustain a marked inflammatory response by the host, leading to fatal outcomes in sensitive organs.
What is Mixed Antiinflammatory Response Syndrome (MARS)?
MARS is a condition where both SIRS and CARS coexist.
where are produced the acute phase proteins?
in liver
Which cytokines are main responsible for transcription of acute proteins?
TNF, IL -1, and IL -6; glucocorticoids; and growth factors stimulate and modulate gene expression
what are the two major acute phase proteins?
SAA and C-reactive protein (CRP)
SAA is involvved in which regulations?
cholesterol regulation
chemotaxis
mediation of inflammatory events
Reference value for healthy neonatal foals and adults, value abnormal
expected SAA concentration in healthy neonatal foals and adult horses is less than 27 mg/L
with values greater than 100 mg/L, suggestive of an infectious process in foal
how do you diagnose the values of SAA
Using the latex agglutination immunoturbidimetric assay
What does C-reactive protein (CRP) do?
CRP can activate complement, induce phagocytosis, and stimulate cytokine and tissue factor expression.
How are acute phase proteins related to the complement system?
They induce bacteriolysis, increase vascular permeability, and enhance opsonization of microbes and damaged host cells.
How do you diagnose the [] of CRP? what is the normal value?
Using radial immunodiffusion, CR P concentrations have been established in healthy foals and adult horses 5 to 14 mg/mL
What is the significance of hyperfibrinogenemia in horses with inflammation?
It is a clinicopathologic finding indicating a response to inflammation.
What is the role of ceruloplasmin and haptoglobin in SIRS?
They bind bacterial nutrient components like copper and iron and neutralize or transport toxic bacterial components.
What happens when SIRS and CARS are appropriately balanced?
Homeostasis resumes in the host.
What do reactive oxygen species commonly originate from?
Mononuclear phagocytes or neutrophils
What are the effects of oxygen free radicals?
They cause molecular damage and induce cytokine production
Which of the following are vasodilators?
a) Angiotensin and endothelin
b) Bradykinin and histamine
c) TxA2 and leukotrienes
d) Complement components
b) Bradykinin and histamine
What is a significant feature of the diagnosis of SIRS?
Specific alterations in heart rate, temperature, and respiratory rate
What triggers the Compensatory Antiinflammatory Response Syndrome (CARS)?
Over-recruitment of antiinflammatory processes
what are the 2 forms of ROS
molecules that contain unpaired electron
hydrogen peroxide (H2O2)
Name the vasoactive mediators
PGs a
NO,
bradykinin = a by-product of activation of the contact coagulation system = VDilator
histamine, =VDilators.
Angiotensin,
endothelin,
TxA2,
leukotrienes (LTC4, -D4, and -E4)
Which values/parameters are measured for dx SIRS?
The diagnosis of SIR S can be made when at least two parameters’ criteria are present
what is the cut value of blood lactate?
2.06 mmol/L
What does Multiple Organ Dysfunction Syndrome (MODS) refer to?
Altered organ function requiring intervention
What characterizes gastrointestinal dysfunction in MODS?
Presence of ileus and intolerance to enteral nutrition
What system is most affected in horses with MODS?
Gastrointestinal
What indicates gastrointestinal dysfunction in horses?
Signs of ileus, including colic and abdominal distension
What defines dysfunction of the coagulation system in MODS?
Excessive procoagulation and loss of controlled fibrinolysis and loss of natural anticoagulant activities
What role do natural anticoagulants play in MODS?
They are rapidly consumed in sepsis
What contributes to cardiac dysfunction in MODS?
Systemic changes and direct effects on the myocardium
What can lead to hepatic injury in MODS?
Altered hepatic perfusion and endotoxin delivery
What represents a unique manifestation of MODS in horses?
Laminitis
What is the primary mechanism leading to acute renal failure in MODS?
Acute tubular necrosis
What causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in MODS?
Thromboembolism and pulmonary edema
When coagulation system is affected by MODS what is the name for the state of clinical coagulopathy?
With prolonged o rexcessive thrombi formation, platelets, coagulation, anticoagulation, and fibrinolytic factors are consumed, balance is lost, andhemorrhage may ensue. This state of clinical coagulopathy is referred to as disseminated intravascular coagulopathy (DIC ).
Which clinical situations fit with diagnostic crietria for DIC at admission?
Approximately 30% of horses with acute colitis, 70% of horses with a colon torsion, and 25% of septic foals
what is the primary mechanism hypercoagulative state DIC?
it is the activation of coagulation with extrinsic coagulation cascade via enhanced expression of membrane tissue factors caused either by pathogen LPS (endotoxin) or indirectly by cytokins
what is the secondary mechanism that leads to DIC?
failure of appropriate fibrinolysis with consumption of anticoagulation factors
In horses, endotoxin appears to favor activation of which two plasminogen activators?
plasminogen activator inhibitor (PAI ) over tissue plasminogen activator (tPA),
What happens to AT and protein C in case of endotomexia that leads to clot formation and inflamamtory responsy?
natural anticoagulants antithrombin (AT) and protein C are rapidly consumed in sepsis or inactivated by neutrophil enzymes released during the inflammatory response
In endotoxemia the decreased AT and protein C along with development of complications such as jugular thrombi, peritoneal adhesions and laminitis results in what?
Correlation of these activities with the development of complications such as jugular thrombi, peritoneal adhesions, and laminitis is significant and is associated with a reduced chance of survival
Serum cardiac troponin concentration is increased in foals with _____________ and horses with __________ lesions that underwent surgical correction
Serum cardiac troponin concentration, a sensitive biochemical marker of acute myocardial injury, is increased in foals with septicemia32 and horses with small intestinal strangulating lesions that underwent surgical correction
Which criteria are used to suspect Disseminated Intravascular Coagulopathy (DIC) in horses?
Thrombocytopenia and prolonged prothrombin time
In horses, what would not be an appropriate criterion for liver dysfunction?
Progressive hyperbilirubinemia
A
cute renal failure is defined as the presence of
azotemia or oliguria, or both, in a normovolemic patient that does not have signs of postrenal obstruction.
What is the primary mechanism leading to acute renal failure in MODS?
Acute tubular necrosis
What is a sign of renal dysfunction in horses?
Decreased urine production
What causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in MODS?
Thromboembolism and pulmonary edema
What is critical illness–related corticosteroid insufficiency (CIRCI)?
Insufficient cortisol response for the stress of illness
What affects neural function in MODS?
Hypoxia, electrolyte derangements, alterations in glucose homeostasis
Likely triggers for ALI and AR DS in horses include
sepsis,
aspiration of gastric contents,
smoke inhalation,
severe trauma,
transfusion reaction
in foals is triggered by bacterial or viral infection
What is crucial in treating MODS in horses?
Addressing the primary initiating cause and controlling inflammation
Which are the clinical signs of ALI and ARDS in horses?
a) Tachypnea
b) Cough
c) Bilateral foamy nasal discharge
d) pulmonary crackles
e) nasal flare
Complete the table
there is inefficient gas exchange evidenced by hypoxemia (defined as
there is inefficient gas exchange evidenced by hypoxemia (defined as one of the following: partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio [PaO2/FIO 2] of <300 mm Hg for ALI and <200 mm Hg for AR DS,
clinical signs of DIC
thrombi
petechiae
ecchymoses
compartmental hemorrhage
diagnosis of DIC obtained if the values are abnormal
thrombocytopenia;
prolonged prothrombin;
activated partial thromboplastin time;
decreased fibrinogen concentration or prolonged thrombin time;
increased fibrin degradation products or D-dimer concentrations;
or decreased antithrombin activity
icterus is a common feature of anorexia in the horse, progressive hyperbilirubinemia would not be an appropriate criterion. which criteria do you use for liver dx?
increased serum sorbitol dehydrogenase
increased γ-glutamyltransferase activities
increased serum bile acid concentration
What is a suggested parameter for cardiovascular failure in horses?
lactatemia;
the presence of hypotension (either decreased systolic or mean arterial pressure [MAP]);
the presence of pathologic arrhythmias, particularly ventricular in origin;
myocardial ischemia (such as increased cardiac troponin concentrations);
loss of heart rate variability;
decreased cardiac output and contractility;
the need for vasopressor therapy.
Serum cardiac troponin increased values in colic patients is excellent to inficate
presence of ischemic intestinal disease and nonsurvival
What are the 2 things that allow you to conclude the presence of laminitis (no radiograph)
A positive response to hoof testers or mitigation of signs following digital nerve block would be sufficient evidence for diagnosis of early acute laminitis
Presence of digital pulse, hoof wall heat and depression of coronary band
In adult horses the quantification of urine is difficult to asses but in foals with urinary kt the mean urine production is
6 ml/kg/hour
What is Sepsis in horses?
The systemic inflammatory response to infection
How does the innate immune system initially prevent infection?
By immediately counteracting with a protective response
What is Septicemia in horses?
Microbial invasion into the bloodstream with systemic respons
What are Pattern-Recognition Receptors (PRRs) in the innate immune system?
Receptors for detecting microbial ligands that detect and discriminate invadors by detecting the PAMPs
What can cause the innate immune system to be overwhelmed by infection?
Severe microbial proliferation and invasion
The innate immune system is composed of
phagocytic cells (principally monocytes, macrophages, and neutrophils) and an extensive array of molecular substances that are present in the circulation, on cell surfaces, and inside cells
Common portals of entry for microbes include the
respiratory, gastrointestinal, and urogenital tracts and the skin. Microbial invasion into the bloodstream, with a concurrent systemic host response, is termed septicemia
Septicemia is often cited as one of the most common causes of illness and death in
neonatal foals
Septicemia in foals primarly involves which type of bacteria?
Gram -
Examples of PAMPs
bacterial cell wall extracts such as :
endotoxin,
peptidoglycan,
lipoteichoic acid,
prokaryotic DNA
What is the significance of the CD14–Toll-like receptor (TLR) relationship in horses?
It is involved in detecting endotoxin, a PAMP
What happens when the innate immune system fails to prevent microbial proliferation?
The infection advances, leading to severe sepsis
What determines the outcome of an infection in horses?
The appropriateness of the host’s defense response
PRRs are divided in 3 maint types, name them
secreted PRRs (defensins)
cell membrane PRRs –> phagocytosis
cell membrane PRRs –> signal transduction
what is the way of diagnosing sepsis?
cytological presence of microbes in normal sterile tissue and isolation of microbes with culture
endotoxin come from where?
Endotoxin come from gram negative (salmonella, E.Coli) that is released when bacteria from the intestinal wall that is compromossied and the bacteria die or reproduce and the most common is LPS pass to the blood stream
beside the intestinal damage which other clinical situations lead to the liberation of endotoxins?
Septic metritis,
pleuropneumonia,
septic peritonitis
what is this molecule produced by the liver: Lipopolysaccharide binding protein (LBP)?
the LPS gets into the blood stream and get’s aggregated in micelles. The LBP extracts the LPS from the micelle in the blood and transports them to various locations
what are the 3 structural domains of endotoxin?
highly variable outer polysaccharide “O-antigenic” region,
a core region consisting mostly of monosaccharides,
and the highly conserved toxic moiety, lipid A
Is the endotoxin directly toxic to mucous membranes and skin?
No, it needs to enter in circulation and aggregate to resemble micelles
What is the CD14?
LBP can present the endotoxin to a host cell and the endotoxin is transferred to CD14 which is a receptor produced by monocytes and macrophages
Like LBP the CD14 can have dual job like either neutralize endotoxin or enhance toxic effect
who produces abundant CD14?
monocytes and macrophages
CD14 cannot work alone and it has to work with another protein, which one?
CD14 does not structurally cross the cell membrane. Thus it must associate with a secondary protein, TLR
Once the CD14-TLR4-endotoxin complex is compiled at cell surface what happens?
Binding of 2 CD14 and TLR4 will activate translocation of nuclear factor κB (NFκB) that will activate genes that code arachidonic acid (PGlandins, tromboxane and leukotrienes) cytokins ( IL -1B, IL-6,TNF), chemotactic peptides (histamine, serotonin, bradykinin) ROS –> inflammation! endotoxemia that can lead to immunosuppression, hemodynamic changes and coagulopathy
Clinical signs of endotoxemia wha is the early hyperdynamic phase?
It happens in 30 to 60 minutes
develop mucous membrane pallor; become depressed, anorectic, tachypneic, tachycardic, and restless; develop fasciculations and mild to moderate signs of colic; and pass loose feces
what happens to the pulmonary tension in the early hyperdynamic phase of endotoxemia?
pulmonary hypertension (increased pulmonary arterial and wedge pressures, and increased pulmonary vascular resistance) and ileus associated with increased levels of thromboxane A2, although other vasoconstrictors likely contribute.
when does it happen the hypodynamic phase of endotoxemia?
within 1 to 2 hrs with depression, anorexia, fever and hypotension
what caractherizes the hypodynamic phase of endotoxemia?
This hypodynamic phase of endotoxemia is caused by decreased systemic vascular resistance from the release of prostaglandins. Mucous membranes are often hyperemic, and capillary refill time is prolonged. With reduced tissue perfusion, the classic “toxic line” develops as a red to blue-purple line (a few millimeters in width) at the periphery of the gums. This is particularly notable at the upper incisors.
what is the endotoxemic dosage of flunixim?
0.25 mg/kg QID (every 8h)
what is flunixim meglumine _____________ _______________ inhibitor
a nonspecific cyclooxygenase inhibitor
what is the advantage of low dose flunixim?
reduced risk of potential toxic side effects and effective inhibition of prostanoid synthesis without completely masking physical manifestations of endotoxemia that are necessary for accurate clinical assessment of the patient’s progress
beside flunixim which other drug is commonly uysed to blockade the lipid peroxidation? what dosage?
dimethyl sulfoxide (DMSO) is frequently used intravenously at doses ranging from 0.1 to 1 g/kg body weight, diluted to at least 10% in isotonic fluid
What is the gold standard for measurement of endotoxin?
the limulus amebocyte lysate (LAL ) assay the plasma, portal circulation, or peritoneal fluid
the limulus amebocyte lysate (LAL ) assay for endotoxin dx is used frequently?
tedious nature makes it impractical as a routine diagnostic test
the limulus amebocyte lysate (LAL ) assay for endotoxin is tedious so how do you diagnose endotomexia?
diagnosis of endotoxemia relies heavily on identification of clinical signs and diagnostic markers in diseases known to be associated with the release of endotoxin
One cardinal diagnostic marker of endotoxemia
profound neutropenia with toxic neutrophil morphology (basophilic cytoplasm, vacuolization, Döhle bodies) with a left shift. Neutropenia will occur within an hour of onset of endotoxemia and is proportionate to the degree of endotoxemia.
Name the clinical features in analysis of endotoxemia
neutropenia with left shift
hyperglycemia
hypovolemia
hyperproteinemia
azotemia
metabilic acidoses with increased anion gap and lactic acidosis
increased creatine phosphokinase
increased GGT
increased troponin
How do you treat endotoxemia?
Remove the cause
When endotoxemia is the result of acute intestinal inflammation or ischemia, translocation of luminal endotoxin might be abated by administering smectite orally (4 ounces orally, twice daily), which absorbs bacteria and bacterial toxins, and by specifically treating the underlying disease, such as surgically removing the ischemic intestine
gram-negative sepsis, tissue débridement and lavage
antiendotoxin antibodies and polymyxin B
Fluidotherapy hypertonic crystalloid fist 2-4 mL/kg (1-2L for 500kg horse) reassess and give 2-4 mL/kg/hr maintenance with isotonic crystalloids
what can you use in foals with E. Coli infection?
Hyperimmune anticore plasma to Escherichia coli J5 can be used in foals for the concurrent treatment of endotoxemia, septicemia, and failure of transfer or passive immunity, given at the dose recommended for treatment of failure of transfer of passive immunity (20 to 40 mL/kg BWT) or in adult horses
what can you use in foals with sakmonella typhimurium infection?
hyperimmune serum from horses vaccinated with the Salmonella typhimurium, Re mutant, has the disadvantage of requiring refrigeration. Dilution of this product with sterile isotonic saline or lactated Ringer solution (1 : 10 to 1 : 20) and administration of the diluted product intravenously over 1 to 2 hours may reduce the risk of another complication: hypersensitivity reactions
what is polymyxin B?
is a cationic antibiotic that, in addition to its bactericidal properties, also binds to and neutralizes endotoxin through direct molecular interactions with the lipid A region
what is the dosage of polymyxin B?
Currently, in horses and foals, the recommended dose of polymyxin B is 1000 to 6000 IU iu/kg BWT, administered intravenously every 8 to 12 hours
Be careful with azotemic patients risk for kidney
