Critical care Medicine: Endotoxemia and DIC Flashcards
What causes endotoxemia in the horse? (according to Dr. PePedro)
Endotoxemia is a systemic disorder that is caused by a horse’s immune response to gram-negative bacteria or any other organism that triggers the innate immune system which then leads to an inflammatory response that cannot by sufficiently contained.
What is endotoxin? When is it released?
A heat-stable toxin associated with the outer membranes of certain gram-negative bacteria, for example LPS (lipopolysaccharide)
It is released during cell membrane lysis or during rapid cell proliferation
How many structural domains does LPS have and what are they?
3:
Polysaccharide O region (outer)
Core acidic polysaccharide
Lipid A region (inner)
Which domain accounts for the serologic differentiation among bacterial species?
O-antigen (outer part)
Very variable among bacterial species
Antigenic stimulus for antibody production and serospecificty
Which domain is most responsible for the toxic effect of endotoxemia?
Lipid A (inside)
FIll in the blanks for this description of the pathophysiology of endotoxemia:
- _______ enters the circulation and binds with LPS-binding protein
- This receptor is rapidly synthesized by the ______ and has a strong affinity for the _______ domain a receptor on mononuclear phagocytes (CD14) .
- Once all three of these around bound together the phagocyte is activated and _______ _________ are produced.
- This leads to hyperactivation of the ________ _________.
- ENDOTOXIN enters the circulation and binds with LPS-binding protein
- This receptor is rapidly synthesized by the LIVER** and has a strong affinity for the **LIPID A domain and to a receptor on mononuclear phagocytes (CD14) .
- Once all three of these around bound together the phagocyte is activated and PRO-INFLAMMATORY MEDIATORS are produced.
- This leads to hyperactivation of the IMMUNE SYSTEM
Which systems can be involved in Stage 1 of Endotoxemia? (i.e. through which systems can bacteria end up in the system)
Gastrointestinal
Respiratory
Integument
Reproductive
Urinary
Endocrine
What are the gastrointestinal conditions that pose a risk for the intiation of stage 1 of endotoxemia?
Colic (abdominal pain) - Severity is usually indicated by the level of pain
Enteritis
Colitis (inflammation of large colon)
Choke
What is the purpose of abdominocenesis? What are you looking for?
It reveals the “Integrity of the abdominal cavity”
Represents the environemnt in the abdominal cavity
To look for cells, blood cells or proteins which have leaked into the abdominal cavity due to injury/damage
What is the disease called when endotoxic colitis is caused by Neorickettsia risticii ?
Potomac Horse Fever
Put these 6 processes in order regarding the progression of disease:
Sepsis, SIRS, MODS, MOF, Endotoxemia
Replace acronyms with words
- Sepsis
- Endotoxemia
- SIRS = Systemic Inflammatory Response Syndrome
- CARS = Compensatory Anti-inflammatory Response Syndrome
- MODS = Multi-Organ Dysfunction Syndrome
- MOF = Multi-Organ Failure
Which drugs can induce colitis? How?
Antibiotics - kill endogenous flora allowing gram - bacteria to proliferate/take over causing colitis and mucosal injjury
NSAIDs (Banamne, Phenylbutazone)- have prostaglandin inhibiting effect resulting in inability for enteric cells to regenerate resulting in ulcergenic lesions in the GIT
What allows endotoxins to gain entry to the portal circulation due to bacterial overgrowth resulting in degeneration of the colonic mucosa?
Carbohydrate overload
What is one the respiratory condition and one respiratory/GI combo condition that pose a risk for the intiation of stage 1 of endotoxemia?
Pleuropneumonia
Choke
What must you do to prevent endotoxemia following/caused by an effusive pneumonia?
Thoracotomy to drain the chest
What are the reproductive conditions that pose a risk for the intiation of stage 1 of endotoxemia?
Retained placenta (most common)
Uterine rupture
Severe metritis
After how much time must you intervene if a horse has retained placenta?
No longer than 2 hours
What are the endocrine abnormalities that predispose a horse to endotoxemia? Describe them.
Equine Metabolic Syndrome: Lipotoxicity (excessive converison of glucose to fat) disrupts insulin receptors to the point of insulin resistance. This is associated with oxidative stress and inflammation, due to i_ncreased levels of cytokine expression_ (IL-6, 8, 10; TNF-alpha) in circulating leukocytes. This results in an exagerrated response to LPS.
Cushing’s Syndrome (Hyperadrenocorticism): Overstimulation of the adrenal glands by ACTH results in corticol synthesis and eventually a hyper-cortisolemic state. Cortisol is immunosuppresive, so when exposed to LPS they have a higher chance of becoming toxic.
Stimulation of which cells by endotoxins initiates stage 2 of endotoxemia? What does the LPS bind to and then what is bound next?
Macrophages
LPS binds to LBP (LPS binding protein) which then binds to CD14 on intravascular macrophages
TLR-4 activates 2 pathways ________ and _____/______ in most animals?
Which of thse is the pro-inflammatory pathway? Which is the anti-inflammatory pathway?
What occurs in the horse making them different from other animals?
MyD88- Pro-inflammatory
TRIF /TRAM - Anti-inflammatory
In horses TLR 4 only triggers the MyD88 pathway. (i.e. it is only pro-inflammatory in horses)
What are the criteria for the diagnosis of SIRS? How many are needed for a posititve diagnosis?
Require at least 2 for diagnosis
Leukopenia (Low [LO’s]), Leukocytosis (High [LO’s]), or >10% bands (immature LO’s)
Hyperthermia or Hypothermia (depending on stage)
Tachycardia
Tachypnea
Evidence of sepsis in foals (because they deteriorate quickly and so can recognize SIRS more quickly than in adults)
What barriers prevent bacteria from translocating into circulation?
Mucosal epithelial cells (physical barrier)
Secrete lysozyme, enzymes and antibodies to limit enteric bacteria from invading the mucosal lining
What disease process can result in the intiation of stage 1 of endotoxemia after an intramuscular infjctions of Banamine?
Clostidium Myocitis aka Gas Gangrene
What causes vasocontriction early in stage 2 of endotoxemia? What type of shock does this cause? What is the clinical presentation of a horse in this stage?
Macrophages stimulating TXA2 and other vasoconstrictors
Hyperdynamic shock
Horse: Pale mucus membranes, tachypnea, other signs of hypoxia
What follows the vasoconstictive phase of stage 2? What is the clinical presentation of a horse in this stage?
Synthesis of cytokines (Il-1, TNF) resulting in an amplification of an endotoxic singal resulting in vasodilation.
Horse will have conjested and darkly hyperemic mucus membranres, and signs associated with low blood pressure
Injury to what structure results in stage 3 of endotoxemia? What follows this damage?
Endothelial cells (by NO degranulation)
Activates procoagulant activity
What vasodilatory substances are produced by endothelial cells? What type of shock does this intitiate?
Prostacycline
Nitric Oxide
Hypodynamic shock
What occurs in stage 4 of endotoxemia?
Vasodilation
Intravascular cellular plugging (creates an ischemic event)
Coagulation
Systemic arterial hypotension
Vascular leakage and injury leading to Protein leakage (edema reaction)
In stage 5 of endotoxemia, the recovery phase, LPS induces ______ which results in the deactivation of mononuclear phagocyte and inhibits ________ cytokines.
T/F: The process above is usually sufficient to overcome endotoxemia so once this stage is reached treatment is not necessary.
In stage 5 of endotoxemia, the recovery ohase, LPS induces IL-10 which results in the deactivation of mononuclear phagocyte and inhibits pro-inflammatory cytokines.
FALSE- probably cannot overcome the disease without treatment
In experimentally induced endotoxemia, why do decreased GIT sounds usually accompany the prolonged CRT and toxic line seen early in the disease process?
GIT takes the first hit when hypovolemia is present or the hyperdynamic state is taking over
T/F: Petecia and echymoses occur in the later stages of endotoxemia, usually accompanying DIC.
True
Equine monocytes when challenged with LPS originating from what bacterium react especially strongly?
E. coli
Match the following symptoms to either the hyperdynamic or hypodynamic stage of endotoxemia:
Congested, dark MMs
White or injected MMs
Strong pulses
Weak Pulses
Fever
Cold exremities
Toxic line
Prolonged CRT
HYPER: White or injected MMs, Strong pulses, Fever
HYPO: Congested, dark MMs, Weak pulses, Cold extremitites, Toxic line, Prolonged CRT
T/F: Tachycardia is a classical sign that the horse is in the hyperdynamic stage of endotoxemia
FALSE
Tachycardia can occur in either stage
What diagnostic changes can be seen in an arterial blood gas analysis in a horse with endotoxemia?
Hypoxemia (low PaO2 and SaO2)
and
Metabolic and Lactic acidosis (increased lactate, HCO3 is low and the pH is low)
In horses flagellin stimulates ______ while in other mamals it stimulates _______ (blanks are types of cells).
Neutrophils
Monocytes
What diagnostic changes can be seen on a CBC in a horse with endotoxemia? Does the severity of these results correlate with the severity of the disease?
Leukopenia
Neutropenia
Left shift
(Degenerative left shift if bad)
Yes, correlates with severity.
What is the major prognostic indicator for endotoxemia? Why?
Glucose (hyperglycemia = very poor prognosis)
Endotoxemia has caused insulin resistance
What indicator reflects whether your treatment for endotoxemia is effective?
Lactate
If fibrnogen is low when a horse comes in with colic, what do you fear may be occuring?
Horse is going into DIC (Fibrinogen should be hihg in inflammatory processes)
One of the goals of tratment for endotoxemia is cardiovascular support. What treatments can you do to achieve this?
Balanced polyionic IVF (LRS, Normosol) at 10-20 ml/kg/hr (for at least 1 hour and administer at least 10L in the first hour)
Alternative: Hypertonic Saline followed by balanced fluids (for 1 L of 7.5% NaCl must give 5-10L of LRS)
Plasma (Hyperimmunized plasma)
What can be given to neutralized LPS in the treatment of endotoxemia?
Polymixin B (binds to Lipid A)
What therapy is necessary but may result in a worsened clinical presentation? What type should be given?
Anti-microbial therapy
Broad spectrum
What can be given to inhibit the synthesis of endotoxin induced mediators (TAXA2 adn PGI2) when treating endotoxemia?
NSAIDs (Flunixin meglumin, low dose)
Aside from causing immune suppression, why are glucorticoids counterindicated to treat endotoxemia?
Cause laminitis
What strong smelling therapy which is a strong anti-inflammatory agent is used to treat endotoxemia? How is it administered?
DMSO
IV but DILUTED!
What IV drug that inhibits TNF-alpha activity in peritoneal fluid significantly decreases the severity of clinical signs of endotoxemia? What side effects may you see with the loading dose of this drug?
Lidocaine
Seizures
What are the 3 major causes of DIC in horses?
Secondary to sepsis and endotoxemia (acute GI dz, localized infections)
Immune-mediated disease
Neoplasia
Horses have very low levels of _________ which makes them more prone to developing DIC.
Antithrombin III
What complication associated with DIC can occur following the placement of a jugular catheter? How can this be prevented?
Jugular thrombophlebitis
Make sure whoever is placeing it is bomb at it, not just one clean stick but also correct suturing, and use a polyurethane IVC
What catheter material would be a terrible choice for a horse in DIC?
Polypropylene (it is the most thrombogenic)
What important diagnostic test must you run with the CBC/chem when investigating DIC?
Platelet count
What test indicates the amount of fibrin formation within the vasculature?
D-Dimers
What specific drug can be given to control the hypercoagulable phase of DIC? What can be given for the hypocoagulable phase?
Low Molecular Weight HEPARIN (LMWH)
Plasma
What Chinese herb is used to treat DIC and why?
Yunnan Baiyae
Has anti-inflammatory and immunosupporessive effects and is used to treat hemorrhages and wounds.
What treatments are counter-indicated for DIC?
Antifibrinolytics (Aminocaproic acid)
Hypertonic Saline (causes hemodilution)
Maybe Hetastarch (controversial)
