Endotoxemia / Sepsis Dr. Schlipf Large Animal Medicine

Front 1

What is the definition of sepsis?

Back 1

The systemic inflammatory response to infection

Front 2

What is the main difference b/w endotoxemia and sepsis?

Back 2

*Endotoxemia refers only to LPS in the blood

Front 3

What are some examples of common sources of sepsis? (5)

Back 3

1) Metritis
2) Pneumonia
3) Pleuritis
4) Septic peritonitis
5) Enteritis & colitis

Front 4

What is the definition of endotoxemia?

Back 4

Only refers to circulating lipopolysaccharide found in gram negative bacteria's cell wall

Front 5

What large animal is very sensitive to endotoxemia?

Back 5

Horses

Front 6

What is the definition of SIRS?

Back 6

An inflammatory response to a variety of clinical insults manifested by two or more of the following: increased heart rate, increased respiratory rate, increased or decreased body temperature, increased or decreased WBC (or demonstratable left shift w/ >10% immature neutrophils)

Front 7

What is CARS?

Back 7

Compensatory anti-inflammatory response syndrome

Front 8

What can SIRS result in if CARS doesn't balance it out?

Back 8

MODS: multi organ dysfunction syndrome
e.g. have pleuritis, but now dealing with renal failure

Front 9

Are hooves considered part of MODS?

Back 9

YES! hooves can get laminitis- hooves are considered an organ
-counts against us when looking at number of organs failing and hence prognosis

Front 10

What causes SIRS?

Back 10

Body has it's normal response to inflammation, but then goes overboard (overproduction of pro-inflammatory cytokines)---> SIRS

Front 11

What is the body's response to SIRS?

Back 11

CARS: supposed to be a balance b/w CARS and SIRS

Front 12

How can you tell when an animal's CARS is actually the one causing problems and not SIRS?

Back 12

When CARS is too intense the animal becomes immunosuppressed = can contribute to mortality in ICU

Front 13

How do you determine if an animal fits the definition for sepsis?

Back 13

Look at biomarkers
-things like LPS binding protein
-endotoxin activity
-procalcitonin
*Lots of different ones out there- very few actually give information on sepsis or prognosis

Front 14

What is the definition of severe sepsis?

Back 14

Sepsis with at least one organ dysfunction or hypoperfusion
e.g. horse that comes in w/ colitis and diarrhea and start having changes in renal values and the next thing you know the horse has laminitis
-poor prognosis

Front 15

True or false. More often than not its the secondary diseases that end up killing animals with severe sepsis.

Back 15

True

Front 16

What does the survival of animals with sepsis depend on?

Back 16

The number and severity of complications associated with the sepsis

Front 17

What is the definition of septic shock?

Back 17

Severe sepsis w/ hypotension that is resistant to adequate fluid resuscitation
-no matter how many fluids you give you can't bring pressure up so have to use vasopressors

Front 18

What is the definition of bacteremia?

Back 18

The presence of viable bacteria in the blood stream
-Get a positive blood culture

Front 19

What is the definition of MODS (Multi-organ dysfunction syndrome)?

Back 19

Impairment of two or more organ systems in an acutely ill patient where homeostasis cannot be maintained without therapeutic intervention

Front 20

What is the starting point of sepsis?

Back 20

Stimulation of the *innate immune response

Front 21

The molecules involved in the innate immune response, which results in sepsis have recently been termed __________.

Back 21

DAMPs: damage-associated molecular pattern

Front 22

What are 3 DAMPs?

Back 22

1) The invading organism (bacteria, virus, fungus etc) origin molecules
2) PAMPs: pathogen associated molecular pattern
3) Alarmins
-calprotectin, proteins released from damaged cells

Front 23

What receptors involved with the systemic inflammatory response recognize specific PAMPs?

Back 23

Toll-like receptors (TLRs) and Nucleotide binding oligomerization domain (NOD) receptors
-Thus, there are a host of TLRs that recognize microbial components ranging from double-stranded viral RNA to LPS and peptidoglycan components of bacterial cell walls

Front 24

TLRs play an important inflammatory role in multiple cell types including ________.

Back 24

Epithelial cells

Front 25

What is the purpose of TLRs? How do they play a role in sepsis?

Back 25

Designed to be protective and eliminate the pathogen, cause cytokine release
-but when inflammatory response is overzealous and becomes systemic it can have deleterious effects on the body

Front 26

What is the first cytokine that comes to mind when you think of viruses?

Back 26

Interpheron

Front 27

The most common source of equine endotoxemia/ sepsis is the __________.

Back 27

Gastrointestinal tract

Front 28

What type of bacteria are present in the small and large intestine?

Back 28

-Small intestine: documented as a prominent source of endotoxin-containing coliform bacteria
-Large intestine: also has high concentrations of other types of bacteria such as Streptococcus species and multiple anaerobic species

Front 29

Is endotoxin the only molecule that causes inflammation on gram-negative bacteria in the GI tract?

Back 29

Nope, other molecules such as flagellin, peptidoglycan and bacterial DNA itself can cause inflammation

Front 30

What is the intestinal mucosa's role in preventing sepsis? (2)

Back 30

1) Plays a critical role as a barrier to limit bacteria and/or their toxins from being absorbed into the systemic circulation
2) Part of body's innate immune defense against sepsis

Front 31

**What is absorbed when the intestinal barrier is disrupted in a horse with gastrointestinal disease?

Back 31

Not only endotoxin but a cocktail of multiple gram positive and gram negative toxins from aerobic and anaerobic bacteria
-makes term endotoxemia somewhat naive to explain syndrome -may account for failure of drugs specific to circulating endotoxin to address sepsis

Front 32

True or false. It is abnormal to have the presence of endotoxins in the equine gastrointestinal tract.

Back 32

False, there are GRAMS of endotoxin in the equine GI tract
-yet micrograms can trigger a response

Front 33

Give a general summary of how sepsis can result in a horse with severe colitis.

Back 33

Alteration in normal mucosa think of all the bacteria & protozoa in there), think of parvo puppy, salmonella in adult cow, e coli in cows all = alteration in mucosa so function is altered & normal protection, inflammation so normally tight junctions are loser====> absorb toxins from GI tract (**not just endotoxin!!!)====> trigger to start the whole process! get inflammation and this takes off: either stay in appropriate area on graph or do we have too much of SIRS or CARS

Front 34

Regardless of the initiating factor of sepsis-related disease processes, the clinical result is what 4 deficits?

Back 34

1) Deficits in tissue perfusion
2) Obtundation
3) Ileus
4) Increased risk of laminitis

Front 35

What are 4 initiating factors of sepsis?

Back 35

1) Endotoxin
2) Other bacterial components
3) breakdown products of endogenous proteoglycans
4) Polypeptides arising from the intestine

Front 36

Several mediators have been implicated in the sepsis-related disease process. What are the 4 cells that produce these mediators?

Back 36

1) Mononuclear phagocytes, including monocytes in peripheral blood
2) Peritoneal macrophages
3) Pulmonary intravascular macrophages
4) Tissue-fixed macrophages
-recent studies also implicate neutrophils and more specifically interactions b/w monocytes and neutrophils

Front 37

Explain the clinical cycle that is seen with sepsis?

Back 37

-poor tissue perfusion (extended CRT)-----> look at mentation (obtunded animal)
-decreased GI sounds (ileus starts to develop)
-laminitis has to be on radar when dealing with a horse that's severely sick (colitis, pleuritis, etc)

Front 38

What are the first immune cells that responds to sepsis-related disease processes?

Back 38

Macrophages, monocytes, pulmonary intravascular macrophages (PIMs)

Front 39

How are the lungs really important in the initial response to endotoxins & toxins in the GI tract?

Back 39

Pulmonary intravascular macrophages (PIMs) are important in initial response

Front 40

Of the numerous inflammatory mediators that have been identified as being related to sepsis, what are the 2 most common?

Back 40

1) TNF alpha
2) Prostaglandins

Front 41

When are the cytokines such as TNFa and interleukins (IL-1) synthesized and released when exposed to endotoxins?

Back 41

Released relatively early and exert their effects by altering the expression of other inflammatory genes, after first binding to specific receptors on target cells

Front 42

Collective cytokine due to endotoxin exposure results in initiation of what 4 things?

Back 42

1) fever
2) Alterations in leukocyte function
3) Activation of coagulation
4) Acute phase response component of systemic response to endotoxins

Front 43

When do TNFalpha concentrations peak in response to endotoxin?

Back 43

Peak serum concentrations detected in 1-2 hours

Front 44

What are 2 interleukins that are important pro-inflammatory agents?

Back 44

IL-1
IL-6

Front 45

What is an important anti-inflammatory interleukin?

Back 45

IL-10

Front 46

What is the function of IL-8?

Back 46

Responsible for cell migration, starts drawing neutrophils to area
-normal response unless overzealous

Front 47

Cyclo-oxygenase-derived metabolites of ___________ are involved in the response of horses to endotoxemia.

Back 47

Arachidonic acid

Front 48

Endotoxemia is associated with a rapid increase in circulating concentrations of stable metabolites of _______ and ______.

Back 48

Prostaglandins and thromboxanes (faciitates aggregation, vasoconstrictor)

Front 49

How can you interfere with the process of metabolites of arachidonic acid causing endotoxemia?

Back 49

Early administration of potent non-steroidal anti-inflamatory drugs (such as flunixin meglumine) reduces the hemodynamic and clinical response to endotoxin as well as plasma concentrations of arachidonic acid metabolites

Front 50

Do endotoxins directly make a horse ill?

Back 50

No, endotoxin is merely a potent trigger of the horse's inflammatory response, and it is the response that ultimately makes the horse ill

Front 51

How can endotoxins initiate a systemic inflammatory response?

Back 51

Have one of many pathogen associated molecules patterns (PAMPs) that are recognized by horse's innate immune system

Front 52

What is the best way to identify/ diagnose sepsis?

Back 52

Currently best identified/ diagnosed on the basis of fulfillment of criteria for SIRS in the presence of a suspected or confirmed infection

Front 53

There is no consensus definition of sepsis in large animal patients. How is SIRS diagnosed in large animal patients?

Back 53

On the basis of meeting 2 or 3 out of 4 of the following clinical criteria: abnormal temperature, heart rate, respiratory rate or a change in the leukon (leukocytosis, leukopenia, or significant left shift)

Front 54

A large animal fits the criteria for SIRS, what diagnostic work-up should be done now?

Back 54

-evaluate for evidence of infection
-evidence using culture and cytology (intracellular bacteria)
- Imaging (thoracic radiographs, abdominal ultrasound)

Front 55

What is a useful biomarker currently in clinical veterinary practice?

Back 55

The blood to abdominal fluid glucose and lactate differential

Front 56

What are the 4 things that we try to direct our therapy for sepsis/ endotoxemia towards?

Back 56

1) Circulatory support
-**fluids (most important)
2) Remove cause of sepsis/ endotoxemia (if you can)
-e.g. strangulating intestine--> damaged mucosa, fix strangulation
3) Neutralize circulating endotoxin
4) Inhibit endotoxin induced inflammation
***START W/ FLUID & SUPPORT

Front 57

What drugs can we use to neutralize circulating toxins in sepsis cases?

Back 57

-Banamine (one of the best)
-steroids
-lidocaine (shown to work on peritonitis, but not all body systems e.g laminitis)

Front 58

What are the 3 goals of fluid therapy in a horse with endotoxemia?

Back 58

1) Replacement of deficits
-volume resuscitation
-rehydration
2) Provision for maintenance needs
3) Provision for on-going loses
*polyionic fluids w/ K+ supplement & other supplements if indicated

Front 59

How do we correct acidemia in a patient with endotoxemia?

Back 59

volume expansion using an alkalinizing solution

Front 60

What are 3 alkalinizing solutions that can be used to correct acidemia in large animals?

Back 60

1) Lactated ringers solution or Normosol-R
2) Bicarbonate supplementation may be necessary
3) Hypertonic saline solution helps restore circulatory volume & then followed by isotonic solutions

Front 61

What are 2 colloidal fluids that can be used in a horse w/ endotoxemia?

Back 61

1) Plasma
-maintain total solids > 4.0g/dL
-Benefit from other protein constituents (AT III, fibronectin)
2) Hetastarch (10ml/kg/day)

Front 62

Why do we give NSAIDs to a horse with endotoxemia? What NSAID do we like to give?

Back 62

Analgesia and anti-endotoxic effects
-Flunixin meglumine

Front 63

What type of agent is pentoxfylline? How does it work?

Back 63

Rheologic agent
-decreases platelet aggregation and TNF and IL-1 in vitro (important mediators of endotoxemia)

Front 64

How is pentoxfylline administered? Why?

Back 64

HAVE TO GIVE IV FORM
-low bioavailability if administered orally in the horse

Front 65

When should aspirin be administered to a horse with endotoxemia?

Back 65

When have thrombotic disorders (DIC)

Front 66

What are 3 reasons to administered heparin to a horse with endotoxemia?

Back 66

1) Laminitis prevention?
2) W/ plasma promotes AT-III activity
3) DIC

Front 67

What's the purpose of administering polymixin B to a horse with endotoxemia?

Back 67

Binds endotoxin
-clinical evidence of efficacy?
-caution when administering to azotemic patient

Front 68

What are 2 cases when antimicrobials should be used in horses with endotoxemia?

Back 68

Bacteremia
Immunosuppression is present

Front 69

What are 2 antimicrobial protocols that can be used in horses with endotoxemia?

Back 69

1) Aminoglycosides and penicillin commonly used
-penicillins may predispose to clostridial colitis
2) Metronidazole
-anti-inflammatory effects

Front 70

What is volume resuscitation? Compare to rehydration.

Back 70

Resuscitation: rapid, initial volume replacement, the initial 1-2 hours of time; hydration occurs over hours of time after you have performed fluid resuscitation (after this perform fluid maintenance)