Chapter 2 - SIRS

Question 1

systemic inflammatory response and failure of multiple organ systems are a

Answer 1

syndrome

Question 2

What is the Systemic Inflammatory Response?

Answer 2

inappropriate and generalized inflammatory response to stimuli, which may or may not result from an infectious process.

Question 3

What is the ultimate goal of the immune system in microbial invasion or tissue damage?

Answer 3

To contain infection, alarm the host, and promote tissue repair

Question 4

What can initiate Systemic Inflammatory Response Syndrome (SIRS)?

Answer 4

Infection,
endotoxemia,
severe trauma,
ischemia,
or hypoxemia

Question 5

What does the host produce to counteract?

Answer 5

cytokines
soluble cytokine receptors
receptor antagonists
prostaglandin E2
corticosteroids

Question 6

What are cytokines in the context of SIRS?

Answer 6

Protein substances that respond to infectious agents or tissue damage

Question 7

Predominance of SIRS may culminate in adverse pathophysiologic events such as (name 4)

Answer 7

1) disseminated intravascular coagulopathy
2) shock
3) organ failure
4) death

Question 8

what are the 2 types of cytokine?

Answer 8

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

Question 9

who produces the proinflammatory cytokines TNF, IL and IFN-γ?

Answer 9

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,

Question 10

what are the main functions of TNF, IL-1 and IL-6?

Answer 10

initiate coagulation, fibrinolysis, complement activation, the acute phase response, and neutrophil chemotaxis.
TNF and IL -1 also induce pyrogenic activities

Question 11

What type of molecule is arachidonic acid

Answer 11

Arachidonic acid is a 20-carbon fatty acid that is a major constituent of the phospholipids of all cell membranes

Question 12

What is the role of arachidonic acid in SIRS?

Answer 12

To be a precursor for eicosanoid synthesis

Question 13

in septic foals that did not survive, IL -___ gene expression was significantly greater than in surviving ones

Answer 13

in septic foals that did not survive, IL -10 gene expression was significantly greater than in surviving ones

Question 14

Endotoxin, TNF, and ILil-1 all upregulate the activity of

Answer 14

phospholipase A2, the enzyme responsible for cleavage of arachidonic acid

Question 15

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).

Answer 15

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).

Question 16

The prostanoids are vasoactive substances: TxA2 and PGF2α what is each one of them?

Answer 16

The prostanoids are vasoactive substances:
TxA2 and PGF2α = Vasoconstrictors
PGI2 and PGE2= Vasodilator

Question 17

The prostanoids PGI 2 and PGE2 are

Answer 17

PGI 2 and PGE2 are vasodilators

Question 18

PGE2 has 2 functions name them

Answer 18

vasodilation and pyrogen

Question 19

What is the key initiation and propagation of SIRS?

Answer 19

invading microorganism release PAMPs or DAMPs

Question 20

what does it mean PAMPS and DAMPs

Answer 20

pathogen-associated molecular patterns [PAMPs])
damage-associated molecular patterns [DAMPs]

Question 21

who recognize the PAMPs and DAMPs and releases endogenous mediators that drive inflammatory response?

Answer 21

Host cell–associated pattern recognition receptors (PRR s)

Question 22

What is the name of multiple organ dysfunction syndrome?

Answer 22

MODS

Question 23

Platelet - Activating Factor (PAF) is released from cell membrane of which ç?

Answer 23

mononuclear phagocytes
endothelial ç
platelets
phospholips by phosphilipase A2

Question 24

The released **alkyl-lyso-glycerophosphocholine **is then acetylated to form PAF. The biologic effects of PAF include

Answer 24

vasodilation,
increased vascular permeability,
platelet aggregation,
and recruitment
and activation of phagocytes

Question 25

What does it mean to be acute phase protein?

Answer 25

An acute phase protein is any protein whose blood concentration significantly increases (or decreases) during an inflammatory response

Question 26

What is the general accepted summary of conditions leading to systemic inflammatory response?

Answer 26

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.

Question 27

What is Mixed Antiinflammatory Response Syndrome (MARS)?

Answer 27

MARS is a condition where both SIRS and CARS coexist.

Question 28

where are produced the acute phase proteins?

Answer 28

in liver

Question 29

Which cytokines are main responsible for transcription of acute proteins?

Answer 29

**TNF, IL -1, and IL -6; glucocorticoids; and growth factors** stimulate and modulate gene expression

Question 30

what are the two major acute phase proteins?

Answer 30

SAA and C-reactive protein (CRP)

Question 31

SAA is involved in which regulations?

Answer 31

cholesterol regulation chemotaxis mediation of inflammatory events diminish fever, phagocytosis, prostanoids synthesis

Question 32

Reference value for healthy neonatal foals and adults, value abnormal for SAA

Answer 32

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

Question 33

how do you diagnose the values of SAA

Answer 33

Using the latex agglutination immunoturbidimetric assay

Question 34

What does C-reactive protein (CRP) do?

Answer 34

CRP can activate complement, induce phagocytosis, and stimulate cytokine and tissue factor expression.

Question 35

How are acute phase proteins related to the complement system?

Answer 35

They induce bacteriolysis, increase vascular permeability, and enhance opsonization of microbes and damaged host cells.

Question 36

How do you diagnose the [] of CRP? what is the normal value?

Answer 36

Using radial immunodiffusion, CR P concentrations have been established in healthy foals and adult horses 5 to 14 mg/mL

Question 37

What do reactive oxygen species commonly originate from?

Answer 37

Mononuclear phagocytes or neutrophils

Question 38

ROS react with unpaired electron and what happens

Answer 38

more radicals are generated molecular damage loss of protein cross linking of DNA lipid peroxidation vasocontriction pain they induce **cytokin production and endothelial adhesion**

Question 39

Which of the following are **vasodilators?** a) Angiotensin and endothelin b) Bradykinin and histamine c) TxA2 and leukotrienes d) Complement components

Answer 39

b) Bradykinin and histamine

Question 40

What is a significant feature of the diagnosis of SIRS?

Answer 40

Specific alterations in heart rate, temperature, and respiratory rate

Question 41

What triggers the Compensatory Antiinflammatory Response Syndrome (CARS)?

Answer 41

Over-recruitment of antiinflammatory processes

Question 42

what are the 2 forms of ROS

Answer 42

molecules that contain unpaired electron hydrogen peroxide (H2O2)

Question 43

Name the vasoactive mediators

Answer 43

**Vasoconstriction:** bradykinin = a by-product of activation of the contact coagulation system = VDilator histamine, =VDilators. Angiotensin, endothelin, TxA2, **Promote vascular leakage are 3:** PAF leukotrienes (LTC4, -D4, and -E4) NO

Question 44

Which values/parameters are measured for dx SIRS?

Answer 44

The diagnosis of SIR S can be made when at least two parameters’ criteria are present

Question 45

what is the cut value of blood lactate?

Answer 45

2.06 mmol/L

Question 46

What does Multiple Organ Dysfunction Syndrome (MODS) refer to?

Answer 46

Altered organ function requiring intervention

Question 47

What characterizes gastrointestinal dysfunction in MODS?

Answer 47

Presence of ileus and intolerance to enteral nutrition

Question 48

What system is most affected in horses with MODS?

Answer 48

Gastrointestinal

Question 49

What indicates gastrointestinal dysfunction in horses?

Answer 49

Signs of ileus, including colic and abdominal distension

Question 50

Who induces MODS?

Answer 50

Sepsis Endotoxemia DIC Ischaemaia Surgery aNestesia Massive trauma Burns Drug reaction Anaphylaxis

Question 51

**What happens to the natural anticoagulants during MODS?**

Answer 51

They are rapidly consumed in sepsis

Question 52

What contributes to cardiac dysfunction in MODS?

Answer 52

cytokines on myocardium and electrolyte disturbances can negatively affect myocardial contraction

Question 53

What can lead to hepatic injury in MODS?

Answer 53

Altered hepatic perfusion and endotoxin delivery

Question 54

Whivh major elements that define dysfunction of the coagulation system

Answer 54

1) Excessive Pro-coagulation 2) 2) Loss of controlled fibrinolysis 3) 3) Loss of natural anticoagulant activities

Question 55

What is the primary mechanism leading to acute renal failure in MODS?

Answer 55

Acute tubular necrosis

Question 56

What causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in MODS?

Answer 56

Thromboembolism and pulmonary edema

Question 57

When coagulation system is affected by MODS what is the name for the state of clinical coagulopathy?

Answer 57

With prolonged o excessive thrombi formation, platelets, coagulation, anticoagulation, and fibrinolytic factors are consumed, balance is lost, and hemorrhage may ensue. This state of clinical coagulopathy is referred to as **disseminated intravascular coagulopathy (DIC ).**

Question 58

Which clinical situations fit with diagnostic crietria for DIC at admission?Name the % of each clinical feature

Answer 58

Approximately 30% of horses with acute colitis, 70% of horses with a colon torsion, and 25% of septic foals

Question 59

what is the primary mechanism hypercoagulative state DIC?

Answer 59

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

Question 60

Are there natural anti-coagulants?

Answer 60

yes anti-thrombin and protein C

Question 61

In horses, endotoxin appears to favor activation of which two plasminogen activators?

Answer 61

plasminogen activator inhibitor (PAI ) over tissue plasminogen activator (tPA),

Question 62

What happens to AT and protein C in case of endotomexia that leads to clot formation and inflamamtory responsy?

Answer 62

they are **rapidly consumed in sepsis** or inactivated by neutrophil enzymes released during the inflammatory response

Question 63

In endotoxemia the decreased AT and protein C along with development of complications such as jugular thrombi, peritoneal adhesions and laminitis results in what?

Answer 63

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

Question 64

what is the cardiac dysfunction biochemical marker?

Answer 64

Troponin concentration

Question 65

Which criteria are used to suspect Disseminated Intravascular Coagulopathy (DIC) in horses?

Answer 65

At least 3 of these: Thrombocytopenia prolonged prothrombin time activated partial thromboplast Diminish fibrinogen concentration Prolonged thrombin time Increment of fibrin degration diminished anti-thrombin activity

Question 66

GI reflux and ileus or obstruction of bile can lead to what type of infection in the liver?

Answer 66

Ascending infection of biliary system with pressure necrosis around bile canaliculi

Question 67

Acute renal failure is defined as the presence of

Answer 67

azotemia or oliguria, or both, in a normovolemic patient that does not have signs of postrenal obstruction.

Question 68

What is the primary mechanism leading to acute renal failure in MODS?

Answer 68

Acute tubular necrosis

Question 69

What is a sign of renal dysfunction in horses?

Answer 69

Decreased urine production 1 ML/kf«g/hr adult and 6 mL/kg/hr foal

Question 70

What causes acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in MODS?

Answer 70

Thromboembolism and pulmonary edema

Question 71

What is critical illness–related corticosteroid insufficiency (CIRCI)?

Answer 71

Insufficient cortisol response for the stress of illness

Question 72

What affects neural function in MODS?

Answer 72

Hypoxia, electrolyte derangements, alterations in glucose homeostasis

Question 73

Likely triggers for ALI and AR DS in horses include

Answer 73

sepsis, aspiration of gastric contents, smoke inhalation, severe trauma, transfusion reaction in foals is triggered by bacterial or viral infection

Question 74

What is crucial in treating MODS in horses?

Answer 74

Addressing the primary initiating cause and controlling inflammation

Question 75

Which are the clinical signs of ALI and ARDS in horses?

Answer 75

a) Tachypnea b) Cough c) Bilateral foamy nasal discharge d) pulmonary crackles e) nasal flare

Question 76

Complete the table

Answer 76

Question 77

clinical signs of DIC

Answer 77

thrombi petechiae ecchymoses compartmental hemorrhage

Question 78

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?

Answer 78

increased serum sorbitol dehydrogenase increased γ-glutamyltransferase activities GGT increased serum bile acid concentration

Question 79

In adult horses the quantification of urine is difficult to asses but in foals with urinary kt the mean urine production is

Answer 79

6 ml/kg/hour

Question 80

What is Sepsis in horses?

Answer 80

The systemic inflammatory response to infection

Question 81

How does the innate immune system initially prevent infection?

Answer 81

By immediately counteracting with a protective response

Question 82

What is Septicemia in horses?

Answer 82

Microbial invasion into the bloodstream with systemic response

Question 83

What are Pattern-Recognition Receptors (PRRs) in the innate immune system?

Answer 83

Receptors for detecting microbial ligands that detect and discriminate invadors by detecting the PAMPs

Question 84

Common portals of entry for microbes include the

Answer 84

respiratory, gastrointestinal, and urogenital tracts and the skin. Microbial invasion into the bloodstream, with a concurrent systemic host response, is termed septicemia

Question 85

Septicemia in foals primarly involves which type of bacteria?

Answer 85

Gram -

Question 86

Examples of PAMPs

Answer 86

bacterial cell wall extracts such as : endotoxin, peptidoglycan, lipoteichoic acid, prokaryotic DNA

Question 87

What is the significance of the CD14–Toll-like receptor (TLR) relationship in horses?

Answer 87

It is involved in detecting endotoxin, a PAMP

Question 88

What happens when the innate immune system fails to prevent microbial proliferation?

Answer 88

The infection advances, leading to severe sepsis

Question 89

PRRs are divided in 3 maint types, name them

Answer 89

secreted PRRs (defensins) cell membrane PRRs --> phagocytosis cell membrane PRRs --> signal transduction

Question 90

what is the way of diagnosing sepsis?

Answer 90

cytological presence of microbes in normal sterile tissue and isolation of microbes with culture

Question 91

endotoxin come from where?

Answer 91

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

Question 92

beside the intestinal damage which other clinical situations lead to the liberation of endotoxins?

Answer 92

Septic metritis, pleuropneumonia, septic peritonitis

Question 93

where does this molecule produced by the liver: Lipopolysaccharide binding protein (LBP) go? Aggregates in what?

Answer 93

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

Question 94

what are the 3 structural domains of endotoxin?

Answer 94

highly variable outer polysaccharide “O-antigenic” region, a core region consisting mostly of monosaccharides, and the highly conserved toxic moiety, lipid A

Question 95

Is the endotoxin directly toxic to mucous membranes and skin?

Answer 95

No, it needs to enter in circulation and aggregate to resemble micelles

Question 96

What is the CD14?

Answer 96

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

Question 97

who produces abundant CD14?

Answer 97

monocytes and macrophages

Question 98

CD14 cannot work alone and it has to work with another protein, which one?

Answer 98

CD14 does not structurally cross the cell membrane. Thus it must associate with a secondary protein, TLR

Question 99

Once the CD14-TLR4-endotoxin complex is compiled at cell surface what happens?

Answer 99

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

Question 100

Clinical signs of endotoxemia wha is the early hyperdynamic phase?

Answer 100

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

Question 101

what happens to the pulmonary tension in the early hyperdynamic phase of endotoxemia?

Answer 101

**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.

Question 102

when does it happen the hypodynamic phase of endotoxemia?

Answer 102

within 1 to 2 hrs with depression, anorexia, fever and hypotension

Question 103

what caractherizes the hypodynamic phase of endotoxemia?

Answer 103

decreased systemic vascular resistance from the release of prostaglandins. Mucous membranes are often hyperemic, CRTtime 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.

Question 104

what is the endotoxemic dosage of flunixim?

Answer 104

0.25 mg/kg QID (every 8h)

Question 105

flunixim meglumine is a____________ _______________ inhibitor

Answer 105

a nonspecific cyclooxygenase inhibitor

Question 106

what is the advantage of low dose flunixim?

Answer 106

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

Question 107

beside flunixim which other drug is commonly uysed to blockade the lipid peroxidation? what dosage?

Answer 107

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

Question 108

What is the gold standard for measurement of endotoxin?

Answer 108

the limulus amebocyte lysate (LAL ) assay the plasma, portal circulation, or peritoneal fluid - not pratical

Question 109

the limulus amebocyte lysate (LAL ) assay for endotoxin dx is used frequently?

Answer 109

tedious nature makes it impractical as a routine diagnostic test

Question 110

the limulus amebocyte lysate (LAL ) assay for endotoxin is tedious so how do you diagnose endotomexia?

Answer 110

diagnosis of endotoxemia relies heavily on identification of clinical signs and diagnostic markers in diseases known to be associated with the release of endotoxin

Question 111

One cardinal diagnostic marker of endotoxemia

Answer 111

**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.

Question 112

Name the clinical features in analysis of endotoxemia

Answer 112

neutropenia with left shift hyperglycemia hypovolemia hyperproteinemia azotemia metabilic acidoses with increased anion gap and lactic acidosis increased creatine phosphokinase increased GGT increased troponin

Question 113

How do you treat endotoxemia?

Answer 113

**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** **Activated carbon** 0.5 mg/kg **Paraffin** **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

Question 114

what can you use in foals with E. Coli infection?

Answer 114

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

Question 115

what can you use in foals with sakmonella typhimurium infection?

Answer 115

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

Question 116

what is polymyxin B?

Answer 116

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

Question 117

what are the risks of polymyxin B?

Answer 117

Polymyxin B is 1000 to 6000 IU iu/kg BWT, administered intravenously every 8 to 12 hours can be nephrotoxic and neurotoxic