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Sepsis/SIRS/MODS > Physiology/Pathophysiology > Flashcards

Physiology/Pathophysiology Flashcards

1
Q

What are the criteria for diagnosis of SIRs in dogs and cats?

A
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2
Q

Define SIRS.

A

A widespread response to an infectious or non-infectious insult and if left untreated can lead to multiple organ failure or death.

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3
Q

List some pro-inflammatory mediators.

Anti-inflammatory mediators?

A
  • ProInflammatory:
    • TNFalpha, IL6, IL1, IL8, prekallikreins, bradykinin, PAF
  • AntiInflammatory
    • IL10, TGF-beta, IL13
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4
Q

What is CARS?

A
  • Compensatory anti-inflammatory response syndrome
    • Characterized by release of anti-inflammatory mediators
    • Production of soluble receptors and receptor antagonists for cytokines such as TNFalpha (thereby decreasing the free circulating amount)
    • Reduction of B and T lymphocyte production
  • Ability to control pro-inflammatory state; however, excessive stimulation of CARS may contribute to immunoparalysis and increased susceptibility to nosocomial infection that can occur in the late stages of sepsis.
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5
Q

What three major systemic effects can arise as a consequence of proinflammatory mediator production?

A
  • Loss of vascular tone
    • Thought to arise secondary to excessive inducible NO synthase
    • Possibly vasopressin or cortisol deficiency
  • Disruption of the endothelial permeability barrier
    • Direct result of cytokine production
  • Stimulation of coagulation
    • Induced by cytokine mediated TF expression on leukocyte surfaces
    • Systemic deposition of fibrin in the microvasculature
    • Endogenous anticoagulant systems (antithrombin, protein C and TFPI) impaired/consumed.
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6
Q

Discuss CRP as a potential biomarker of sepsis.

A
  • Acute phase protein produced by the liver in response to inflammatory cytokine release
  • Peaks 36-50 hours after secretion
  • CRP levels may reflect the severity of the inflammatory process, but these levels have not been shown to differe between survivors and non-survivors

Because of its prolonged half life (19 hours) and lack of specificity, is not considered an ideal marker for sepsis diagnosis

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7
Q

Discuss procalcitonin (PCT) as a potential biomarker of sepsis.

A
  • Precursor molecule to calcitonin, normally produced by thyroid
  • In sepsis, thought to arise from mononuclear leukocytes after endotoxin/cytokine stimulation
  • Has been shown to increase iNOS mediated NO release and may play a role in amplification of inflammation
  • In some studies, PCT levels correlate with disease severity and may have prognostic value in people with sepsis, septic shock
  • Overall thought to be a superior biomarker when compared to CRP
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8
Q

Explain the findings of hyperglycemia and hypoglycemia in a patient with SIRS.

A
  • Hyperglycemia
    • Initially seen earlier in the phase of disease; thought to occur secondary to altered carbohydrate metabolism with increased gluconeogenesis causing early hyperglycemia
  • Hypoglycemia
    • Arises later, when glucose utilization begins to exceed production
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9
Q

What 3 things are cats more likely to manifest than dogs as part of the clinical response to SIRS?

A
  • Hypotension
  • Hypoglycemia
  • Hyperbilirubinemia
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10
Q

Define sepsis.

A

The clinical syndrome caused by infection and the host’s systemic inflammatory response to it. May be of bacterial, viral, protozoal, fungal origin.

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11
Q

What is the reported mortality rate for sepsis in veterinary medicine?

A

20-68%

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12
Q

Define MODS.

A

Physiologic derangements of the endothelial, cardiopulmonary, renal, nervous, endocrine, microcirculatory and gastrointestinal systems associated with progression of uncontrolled systemic inflammation and DIC.

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13
Q

Define septic shock.

A
  • Acute circulatory failure and persistent arterial hypotension despite volume resuscitation.
  • Arterial hypotension:
    • Systolic <90mmHg, MAP <60mmHG
    • OR reduction in systolic BP of >40mmHg from baseline despite adequate volume.
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14
Q

What is PIRO?

A
  • Concept developed to stage sepsis and describe clinical manifestations of the infection and host response to it.
  • P: predisposition
  • I: insult/infection
  • R: response
  • O: organ dysfunction
  • Attempts to incorporate patient factors with the microbial insult in order to stage the disease process and identify factors that may contribute to morbidity and mortality.
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15
Q

What are common sources for gram negative sepsis?

Gram positive sepsis?

A
  • Gram negative sepsis
    • GI and genitourinary systems
  • Gram positive sepsis
    • Skin, injured soft tissue, intravenous catehters
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16
Q

Briefly discuss the development of loss of vasomotor tone associated with sepsis.

A
  • Loss of homeostatic balance between endogenous vasoconstrictors and vasodilators occurs
  • Over-production of NO major contributing factor
    • Powerful smooth muscle relaxant
  • NO is overproduced in response to stimulation with endotoxin, TNFalpha, IL1 and PAF–>high levels of iNOS accumulate and generate high levels of NO, contributing to the signs of vasodilatory shock.
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17
Q

Briefly discuss the development of coagulation abnormalities in septic patients.

A
  • Bacterial infection and host inflammatory cytokines upregulate production of tissue factor that combines with factor VIIa to initiate the coagulation cascade
    • Can also trigger elaboration of inflammatory cytokines and platelet activation
  • Typically initiation of coagulation cascade will trigger counter-regulatory mechanisms
    • In septic patients, downregulation of antithrombin, TFPI, tPO are inhibited, inhibiting natural anticoagulant and fibrinolytic processes
    • Protein C/S pathway also inhibited, leading to a reduction of the normal activated protein C anticoagulant and anti-inflammatory effects.
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18
Q

What is the initial coagulation state seen in sepsis? What does it progress to?

A
  • Initially a procoagulant and anti-fibrinolytic state initially
  • Progression over time to a hypocoagulable state depends on
    • Host protein synthesis, effectiveness of natural coagulation inhibitors, virulence of invading organism and resolution of the inflammatory source
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19
Q

Briefly discuss the development of alterations in the endothelium and increased vascular permeability in sepsis.

A
  • Alterations caused by multiple mechanisms including:
    • Endothelial dysfunction
    • Alterations and damage to the endothelial glycocalyx
    • Rheologic changes to RBC
    • Leukocyte activation
    • Microthrombosis
    • Loss of vascular smooth muscle autoregulation
  • Decreased functional capillary density, increased diffusional distance for oxygen, and heterogenous microvascular blood flow all lead to alterations in tissue oxygen extraction and tissue hypoxia.
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20
Q

What is cytopathic hypoxia?

A
  • The development of mitochondrial dysfunction that can arise in septic patients
    • Neutrophils activate mitochondrial dysfunction pathways ultimately resulting in intrinsic derangements in cellular energy metabolism
    • Cytopathic hypoxia was developed to explain the disconnect between adequate oxygen delivery and poor utilization of oxygen at the tissue level.
  • In addition to their critical role in oxidative phosphorylation, mitochondria are also involved in apoptotic pathways and cell death.
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21
Q

What are the most commonly implicated organisms in sepsis in dogs and cats?

A

Gram-negative enteric bacteria

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22
Q

What are the 5 “bundles” commonly utilized for management of sepsis?

A
  1. Lactate
  2. Samples for culture
  3. Early source control and early antibiotic administration
  4. Treat hypotension with fluids and possibly vasopressors
  5. Target central venous pressure/central venous pressure and ScvO2
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23
Q

When choosing an empiric antibiotic, what should you take into consideration?

A
  • Location of infection (ability of antibiotic to penetrate into that site)
  • Suspected bacterial flora
  • Community versus nosocomial source
  • Duration of hospitalization
  • Previous exposure to antimicrobials
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24
Q

What is the difference between SVO2 and ScvO2?

A
  • SVO2
    • Venous blood in the pulmonary artery=pooled blood from the entire body
    • Can be viewed as a result of the overall difference in oxygen delivery and oxygen consumption (DO2-VO2), and therefore a marker of global oxygen debt
  • ScvO2
    • Central venous oxygen saturation–blood in the cranial vena cava, reflective of oxygen delivery and use in the head and upper body

In health, ScvO2 is < SVO2 by ~2%.

In shock states, this relationship can reverse (ScvO2 can be higher than SVO2) because of redistribution of blood flow from the splanchnic circulation to the coronary and cerebral vascular beds.

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25
Q

With goal directed therapy, what ScvO2 should one target? SVO2?

A
  • ScvO2
    • 70% or greater
  • SVO2
    • 60% or greater
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26
Q

Discuss the “one hit,” “two hit” and the “sustained hit” theories of MODs.

A
  • One Hit Theory
    • Degree of physiologic insult resulting from a primary event can be sufficient to create a massive inflammatory reaction with consequent detrimental effects on the function of organs distant to the site of the initial injury.
  • Two Hit Theory
    • Priming insult followed by a secondary insult which may seem small (such as a catheter related infection); induces enhanced inflammation and immune dysfunction.
  • Sustained Hit Theory
    • Initial immune dysfunction may be augmented by ongoing inflammation in the GI tract which can drive a patient to MODS; ventilator associated pneumonia etc.
    • Continuous insult may cause the initial injury and sustain the dysfunction.
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27
Q

Discuss the pathogenesis of immune dysregulation in the development of sepsis and MODs.

A
  • Initial activation of PRRs (such as TLRs) on immune cells by PAMPs or DAMPs initiates signaling cascades through NFKB.
  • NFKB signaling leads to formation of acute phase protein, iNOS expression and production of proinflammatory cytokines/chemokines.
  • The proinflammatory cytokines lead to conditions favoring the diapedesis of circulating defense cells, extravasation of plasma, vasodilation, increased capillary permeability….
  • Death of cells by necrosis, the release of cytosolic and nuclear components and the degradation of proteoglycans into the ECM provides multiple new DAMPs, accerlating innate immune system activation and stimulating production of even more cytokines/chemokines.
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28
Q

Release of ____ are early events in the release of proinflammatory mediators, whereas _____ are released later and prolong the inflammatory response.

A
  • TNFalpha and IL1
  • IL6 and IL8
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29
Q

What is HMGB-1?

A
  • A protein released by active innate immune cells as well as necrotic cells
  • Acts to promote monocyte TF expression and inhibit protein C activation.
  • Mediators enter circulation and travel to other organs resulting in further cellular dysfunction
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30
Q

What is the “crosstalk” hypothesis as it applies to MODs?

A
  • Posits that organ dysfunction is most likely to occur when reduced barrier function, impaired local immunity and altered intestinal microflora all coexist
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31
Q

Sepsis cardiomyopathy is characterized by…

A
  • Early contractile dysfunction leading to biventricular dilation
  • Reduced ejection fraction and fractional shortening
  • Hypotension, often despite fluid therapy
  • Decreased response to catecholamines
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32
Q

Acute kidney injury has been documented to occur in __% of dogs with naturally occurring sepsis, with only __% of affected dogs surviving to discharge.

A

12%, 14%

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33
Q

What are the RIFLE criteria for AKI?

A

AKI was asociated with an overall increase in hospital mortality with each RIFLE category independently associated with increasing odds of mortality.

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34
Q

What is the characteristic histologic finding in sepsis induced AKI?

A

Marked reduction in kidney function with only mild histologic changes in the kidney

This is in stark contrast to AKI due to many nephrotoxins/ischemia where there is diffuse glomerular or tubular damage with extensive necrosis.

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35
Q

What are some proposed mechanisms for the development of sepsis induced AKI?

A
  • Ischemia/reperfusion injury
    • Sepsis induced AKI can occur in the prsence of normal or even increased renal blood flow
    • Abnormal distribution of blood flow might be occurring, resulting in flow favoring the cortex
    • ***Factors other than altered hemodynamics may be responsible, although microvascular abnormalities cannot be entirely ruled out…***
  • Inflammation
    • Following tissue injury at the site of sepsis, cells release DAMPS that result in further pro-inflammatory responses in distant organs
  • Oxidative stress
    • Geneartion of ROS associated with sepsis may contribute to AKI
  • Epithelial Dysfunction
    • Poorly controlled inflammatory response within the kidney results in widespread renal tubular epithelial dysfunction
  • Sublethal Injury
    • Sublethal cellular injury will result in disruption of cellular function, particularly on the transport processes
    • Combine to produce renal dysfunction in the absence of histopathologic abnormalities
36
Q

Explain how epithelial dysfunction may contribute to a reduction in GFR in sepsis induced AKI.

A
  • Activation of the tubuloglomerular feedback mechanism within the kidney
  • Tubular dysfunction will result in a lack of NaCl reabsorption in the proximal tubule
  • Detected as an increase in Na and Cl delivery to the macula densa in the distal tubule
  • Increased NaCl concentration will result in widespread vasoconstriction of the afferent arterioles and a subsequent drop in GFR
37
Q

What occurs during sublethal injury of sepsis induced AKI that leads to disruption of cellular function without histologic abnormalities?

A
  • Renal tubular cells undergo repair, regeneration and proliferation
  • In the repair phase
    • Cells injured beyond recovery undergo death and exfoliation with an associated infiltration of mononuclear cells
  • Regeneration phase
    • Stem cells appear that are though to rise in the kidney
  • Proliferation
    • Proliferation of surviving tubular cells under the influence of growth factors followed by cellular differentiation to produce normal epithelial cells
38
Q

What are the levels of the IRIS AKI scoring system?

A
39
Q

List 5 proposed mechanisms that may lead to MODS. Which are thought to be the prevailing mechanisms?

A
  1. Cell/tissue hypoxia
  2. Induction of cellular apoptosis
  3. Translocation of microbes or components of microbes from the GI tract
  4. Immune system dysregulation
  5. Mitochondrial dysfunction

**Immune system dysregulation and mitochondrial dysfunction are presumed to be the most important mechanisms**

40
Q

Define immune system dysregulation.

A

The imbalance between proinflammatory and anti-inflammatory counterregulatory mechanisms.

41
Q

What is immunoparalysis?

A

An unchecked CARS response can lead to immunoparalysis (immune system dysrgeulation) leaving the host vulnerable to further injury and infection.

42
Q

Hepatic damage caused by sepsis/SIRS is typically divided into 2 stages. What are these stages?

A
  • Primary stage
    • Septic shock results in hepatic hypoperfusion leading to decreased protein synthesis, lactate clearance, gluconeogenesis and glycogenolysis
  • Secondary stage
    • Results from Kupffer cell activation and subsequent proinflammatory cytokines, chemokines, ROS and NO leading to further liver damage and dysfunction

Hepatic dysfunction with MODS is often defined as hyperbilirubinemia in the absence of pre-existing liver disease.

43
Q

How is bacterial translocation defined as it relates to MODs and what are the two proposed mechanisms for its development?

A

The process by which intestinal bacteria or candida cross the intestinal mucosal barrier to reach mesenteric lymph nodes.

  • Alteration in the normal GI flora
    • After a severe insult such as polytrauma or cardiac arrest, the normal gut flora is destroyed immediately and the number of intestinal pathogenic bacteria gradually increases
  • Physical disruption of the gut mucosal barrier
    • Thought to be caused by inflammatory mediator, endotoxin and NO induced changes in and decreased production of tight junction proteins
44
Q

In addition to bacterial translocation, what other proposed effects does sepsis have on the gastrointestinal tract?

A
  • Decreases in number/strength of jejunal contractions, decreased net absorption of water, electrolytes and nutrients from the jejunum, decreased colonic absorption of water and sodium, and increased colonic motility and contractions
  • Can lead to diarrhea, dehydration and electrolyte abnormalities
45
Q

What are two proposed mechanisms for sepsis induced cardiac dysfunction?

A
  • Endotoxin, cytokines, and calcium leack from the SR, ultimately causing a decrease in myocardial cell contractility
  • Proinflammatory complement protein C5a produces ROS
    • NO production leads to decreased cardiac contractility by downregulation of beta adrenergic myocardial receptors and decreasing cytosolic calcium
46
Q

Sepsis induced encephalopathy is the most common form of encephalopathy in people; briefly explain the pathogenesis.

A
  • Initially the BBB is intact, protecting the brain from systemic inflammation
  • Stimulation of vagus nerve by inflammatory mediators can ultimately result in breakdown of BBB
  • Microcirculatory dysfunction can also occur, along with coagulopathy and changes in vascular tone.
  • SAE thought to decrease the vasodilatory response of the cerebrum, leading to impairment of cerebral autoregulation of blood flow
47
Q

Define CIRCI.

A
  • Inadequate corticosteroid activity relative to illness severity
  • Describes reversible dysfunction of any aspect of the hypothalamic-pituitary-adrenal access caused by proinflammatory cytokines
  • Corticosteroid tissue resistance increases in sepsis, therefore corticosteroid receptor binding may be impaired.
48
Q

List 4 risk factors for dogs becoming carriers of MDR E.coli during hospitalization.

A
  1. Hospitalization for more than 6 days
  2. Treatment with a cephalosporin before admission
  3. Treatment with a cephalosporin for less than 1 day
  4. Treatment with metronidazole while hospitalized
49
Q

What are three important guidelines for prevention and control of nosocomial infections?

A
  • Methods needed to prevent cross-contamination and to control potential sources of pathogenic microorganisms that can be transmitted from patient to patient or hospital personnel to patient
  • Guidelines to direct the appropriate use of prophylactic, empiric, and therapeutic antimicrobial use
  • Strategies to limit the entrance/spread of MDR pathogens should be developed and targeted against organisms known to be prevalent in individual institutions
50
Q

What are the two main mechanisms by which neutrophils kill invading pathogens after activation of their PRR by a PAMP/DAMP?

A
  • Degranulation
    • Phagocytosis of the organism and fusion with an intracytoplasmic phagosome–>cytotoxic molecules and production of ROS destroy the organism and trigger apoptosis of the neutrophil
  • NET formation
    • Nuclear material including DNA and histones combine with cytotoxic molecules from cytoplasmic granules; expleed from the cell into the extracellular space
    • “ensnares” and kills microorganisms while limiting the spread of cytotoxic molecules to prevent damage to regional tissues
    • NETosis–programmed death of neutrophil
51
Q

Discuss the production of lactate. What happens in periods of hypoxia?

A
  • Glycolysis
    • First step of glucose metabolism; is an anaerobic process
      • Process by which 1 mole of glucose is oxidized to pyruvate, ATP and NADH
        • Hydrogen ions are produced during this step
      • Pyruvate enters the mitochondria and is converted to acetyl CoA which goes through the TCA cycle, the electron transport chain, and oxidative phosphorylation to produce ATP
      • Under aerobic conditions, only a small amount of pyruvate is converted to lactate by lactate dehydrogenase.
    • Lactate can either be converted back into pyruvate in local/distant tissues and oxidized to produce energy OR converted back into glucose by gluconeogenesis
  • In periods of hypoxia, tissues are forced to use glycolysis as the sole source of energy production.
    • If there is a cellular oxygen deficiency, the TCA cycle and oxidative phosphorylation are slowed and pyruvate and NADH build up, which hinders ongoing glycolysis
    • To allow glycosis to continue, pyruvate and H+ ions are removed by increased conversion of pyruvate to lactate
    • If anaerobic conditions are widespread, other tissues are unable to convert the lactate to pyruvate or glucose to use for energy production
52
Q

Discuss the relationship between lactate and acidosis.

A
  • The metabolic acidosis associated with lactate production is due to ATP use, not lactate production!
    • Glycosis produces the lactate ion, not lactic acid
  • When the ATP made by glycolysis is utilized, H+ is released into the cytosol.
  • When oxygen supplies are insufficient, H+ accumulates because it cannot be utilized for the electron transport chain and oxidative phosphorylation
  • Acidosis from lactate production is mostly due to reduced H+ consumption, not increased lactate production.
53
Q

What organs are primarily responsible for lactate clearance?

A
  • Liver (50%)
  • Kidneys (20-30%)
54
Q

What are D versus L lactate?

A
  • L-lactate is the lactate produced by cellular metabolism
    • Predominant form produced by mammalian cells
    • Only form able to be standardly measured
  • D-lactate is formed by bacterial glucose metabolism
    • Rare cause of lactic acidosis
    • Should be considered a s differential in patients with a GI disturbance and acidosis but a normal l-lactate
55
Q

List the types of hyperlactatemia.

A
  • Type A (tissue hypoxia/hypoperfusion)
  • Type B
    • BI: underlying disease
    • B2: drugs/toxins
    • B3: mitochondrial disease
56
Q

Discuss Type A hyperlactatemia.

A
  • Occurs d/t increased oxygen demand or decreased oxygen delivery
  • Increased O2 demand
    • Muscle activity such as exercise, struggling, shivering, trembling, tremors, seizures
    • PHysiologic hyperlactatemia should resolve quickly once muscle activity ceases
  • Decreased O2 delivery
    • MOST COMMONLY associated with systemic hypopersusion leading to decreased DO2
    • At some point, tissue VO2 exceeds the ability of DO2 and anaerobic metabolism occurs
    • Causes include systemic hypoperfusion, local hyperperfusion, severe anemia (PCV <10-15%), severe hypoxemia, CO poisoning
57
Q

Broadly discuss type B lactic acidosis (not necessarily each of the types individually…)

A
  • Occurs when oxygen delivery is adequate but altered carbohydrate metabolism or mitochondrial function exists.
58
Q

Describe type B1 lactic acidosis.

A
  • Consists of disease processes believed to be creating lactic acidosis not due to hypoperfusion but possibly due to decreased lactate clearance
    • Sepsis/SIRs
    • Neoplasia
    • Diabetes mellitus
    • Severe liver disease
    • Thiamine deficiency
    • Pheo
59
Q

Describe type B2 lactic acidosis.

A
  • Arises due to drugs/toxins that interfere with oxidative phosphorylation
  • WIDE LIST
    • Corticosteroids!!!
    • Activated charcoal
60
Q

Describe Type B hyperlactatemia.

A
  • Congenital errors in metabolism
  • Mitochondrial myopathies have been reported in the JRT, GSD and Old English Sheepdog
61
Q

Plasma lactate clearance has been evaluated as a prognostic indicator. Approximately how fast should you expect lactate to be decreasing with appropriate volume resuscitation and what if it does not?

A
  • Decrease by half every 1-2 hours
  • If it doesn’t should raise suspicion for another source of lactate such as ongoing hypovolemia, maldistributive shock, obstructive shock or an internal focuse of ischemia or neoplasia
62
Q

Define relative adrenal insufficiency (RAI)

A
  • Describes septic patients with either unexpectedly low basal plasma cortisol concentrations or those whose response to exogenous ACTH was deemed inadequate regardless of basal cortisol concentration
63
Q
A
64
Q

What are some proposed mechanisms for the development of CIRCI?

A
  • Inhibition or damage of the hypothalamus, pituitary or adrenal glands by cytokines, reactive oxygen species, hemorrhage or other deleterious events during septic shock, leading to inadequate cortisol production or inadequate response to administered ACTH
  • Systemic inflammation inhibits GR-cortisol binding, impairs translocation of the complex to the nucleus and alters cortisol-dependent gene transcription.
65
Q

According to the SSC guidelines, when is it appropriate to treat for CIRCI?

A

Glucocorticoid treatment in sepsis should be reserved for patients in fluid-loaded, vasopressor-resistant septic shock.

66
Q

What are the major determinants of MAP?

A
67
Q

Fill in the chart with +++ for receptor activity, and increase or decrease for remaining variables.

A
68
Q

What are the 3 subclasses of adrenergic receptors, where are they located, and what effect would you expect with stimulation of each?

A
  • Alpha-adrenergic receptors
    • Located on smooth muscle cells and in small amounts on myocardial cells
    • Stimulation of alpha receptors on the vascular muscle causes vasoconstriction and increases blood pressure
    • Stimulation of myocardial alpha receptors may lead to positive inotropy
  • Beta-adrenergic receptors
    • Beta-1 primarily in the myocardium
    • Beta-2 peripheral vascular and bronchial smooth muscle
    • Positive inotropic and chronotropic effects within the myocardium
    • Relaxation of smooth muscle in the bronchial tree and vasculature
  • Dopamine receptors
    • Smooth muscle of renal, coronary, splanchnic and cerebrovascular beds
    • Stimulation leads to inhibition of norepi release from sympathetic nerve terminals, leading to vasodilation of local vessels
69
Q

What is the recommendation of the SSC guidelines for management of hypotension despite fluid resuscitation?

A
  • Norepinephrine as first choice vasopressor to maintain MAP >/= 65mmmHg
  • Epinephrine administration when an additional agent is needed
  • Vasopressin can be added to norepi to raise the MAP to goal or decrease the norepi dose, but should not be used as the initial vasopressor
  • Dopamine is not recommended except in highly selected circumstances
70
Q

What are the most potent stimuli for AVP (ADH, vasopressin) release?

A

Increased plasma osmolality, decreased blood pressure, decrease in circulating blood volume

71
Q

What are the classes of vasopressin receptors, what do they do, and how?

A
  • V1 receptors
    • Vascular smooth muscle
    • Vasoconstriction at high doses
      • Gprotein coupled activation of phospholipase C which activates voltage gated calcium channels, increasing intracellular Ca
      • Inactivation of potassium-ATP channel leading to depolarization and opening of voltage gated calcium channels, increasing intracellular Ca
    • Vasodilation in some vascular beds (cerebranl, renal, pulmonary, mesenteric) at low doses
      • Likely mediated by nitric oxide
    • Also on platelets, faciliting thrombosis
  • V2
    • Basolateral membrane of distal tubule, principle cells of cortical/medullary renal collecting duct
      • Couples with the G signaling pathway, increasing intracellular cAMP
      • FUsion of aquaporin-2-bearing vesicles
      • Regulates water homeostasis in 2 ways:
        • Regulating fast shuttling of aquaporin 2 to cell surface
        • Stimulating synthesis of more aquaporins
    • Stimulates release of platelets from bone marrrow and enhances release of vWF and factor VIII from endothelial cells
  • V3
    • Anterior pituitary
    • Activate G protein to release intracellular Ca
    • Activation stimulates release of adrenocorticotropic hormone
    • Responsible for actions of AVP on the CNS where they function as a NT
  • Oxytocin receptor
    • Equal affinity for AVP and oxytocin
    • Leads to smooth muscle contraction
72
Q

Discuss actinomyces and nocardia.

A

Actinomyces is part of the normal flora in dogs/cats; Nocardia is ubiquitous in the environment

73
Q

Briefly discuss the structure and pathogenecity of gram positive bacteria.

A
  • Transpeptidases=penicillin binding proteins in cell wall
    • Responsible for building/maintenance of the cell wall
  • Hydrolase enzymes (Beta lactamases)
    • Within cell wall; attack b-lactam antibiotics and prevent binding to PBPs in normally susceptible bacteria
  • Peptidoglycan
    • Basic structural component of cell wall
    • Relased during infection, reaches systeic circulation, exhibits pro-inflammatory activity
  • Lipotechoic acids
    • Within cell wall; structural/adherence functions
    • Induces proinflammatory cytokine response, production of NO, cardiovascular compromise
74
Q

What is the mechanism of b-lactam resistance in staphylococci?

A
  • Mediated by the mecA gene that encodes production of a modified PBP
  • Normally, b-lactams bind to prevent bacterial cell wall development
  • The modified PBP has low affinity for b-lactams and therefore, cell wall synthesis is not inhibited by these antimicrobials
75
Q

Briefly discuss the pathogenicity and structure of gram negative organisms.

A
  • Endotoxin
    • LPS; accounts for 75% of gram-negative cell membrane
    • Lipid A is the toxic moiety of endotoxin; induces wide range of inflammatory responses
  • Flagella–allow for chemotaxis
  • Pili/fimbriae–act as adhesins, which for many bacteria are vital to ability to cause disease
76
Q

Identify the fungi.

A

A: Blasto

B: Histo

C: Coccidiodes

D: Crypto

77
Q

Discuss the difference in development of effusive versus noneffusive FIP.

A
  • FIP is caused by a mutation of the feline coronavirus
    • Mutation associated with ability to replicate inside macrophages and possibly the loss of the ability to replicate within the enterocytes
  • Cats with poor cell mediated immunity develop pyogranulomatous vasculitis because of the deposition of antigen-antibody complexes within the venular epithelium
    • Pleural/peritoneal effusion occur
  • Cats with an intermediate cell mediate response are able to slow replication of the virus, with subsequent granuloma formation in a variety of tissues (non-effusive FIP)
    • May deteriorate to effusive FIP if CMI response wanes
78
Q

What were the conclusions of a 2008 JVIM study by Goddard et al evaluating white blood cell changes in dogs with CPV?

A
  • The lack of a lymphopenia on admission and at 24 and 48 hours post admission was found to have 100% PPV for survival
  • Nonsurvivors failed to develop a degenerate left shift, continued to have significant leukopenia, lymphopenia, eosinopenia and monocytopenia at 24 and 48 hours post admission
  • Severe neutropenia was not a useful prognostic indicator
79
Q

What are MSCRAMMS?

A
  • Microbial surface compnenets recognizing adhesion matrix molecules
    • Expressed by organisms that commonly cause infectious endocarditis, convey an ability to adhere to damaged valves.
80
Q

What is urosepsis? What is the most commonly associated organism?

A
  • Clinical condition that occurs secondary to a systemic bacterial infection originating from the urogenital tract and the associated inflammatory response
  • E.coli most common; 50%; 1/3 gram-positive cocci, remaining gram-negatives.
81
Q

What is the most commonly reported cause of urosepsis in surgical patients?

A

Pyometra

82
Q

With regards to mastitis, what typical changes are seen with staph infections? Strep? E.coli?

A
  • Staph: abscessation and gangrene
  • Strep: diffuse, spread into other glands
  • E.coli: abscessation, septic mastitis
83
Q

Discuss necrotizing soft tissue infections and toxic shock syndrome.

A
  • NSTI
    • Term used to describe subset of soft tissue infections involving skin, SQ tissue, muscle and fascia that cause vascular occlusion, ischemia and necrosis
    • Progressive, rapidly spread along tissue planes and lethal if uncontrolled
  • TSS
    • Acute, severe, systemic inflammatory response initiated by a microbial infection at a normally sterile site, usually exotoxin-releaseing Staph or Strep
    • Manifests as an acute, early occurrence of circulatory shock and MODS
    • In peopole, commonly associated with necrotizing fascitis
84
Q

What are the types of NSTI?

A
85
Q

Discuss the key pathophysiologic process of NSTI.

A
  • Angiothrombotic microbial invasion with liquefactive necrosis of the superficial fascia and soft tissue
  • Occlusion of nutrient vessels can lead to extensive undermining of apparently normal appearing skin, followed by gangrene of the SQ fat, dermis, and epidermis, evolving into ischemic necrosis
86
Q
A

Sepsis/SIRS/MODS (3 decks)

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