Sepsis/SIRS/MODS > Pathophysiology > Flashcards

Pathophysiology Flashcards

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1
Q

What forces govern fluid flux between the different body compartments?

A

Interstitial - intracellular –> osomlarity
Intravascular - intracellular –> osmolarity
Intravascular - interstitial –> hydrostatic and osmotic (Starling)
Lymphatic and intracellular –> hydrostatic + driving

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2
Q

What is the normal hydrostatic pressure in the interstitium?

A

0 / slightly subatmospheric due to lymphatic drainage

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3
Q

Where is the thermoregulatory control center located in the body?

A

Preoptic area of the anterior hypothalamus.

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4
Q

What generates most of the body heat and which animals have poorly developed thermoregulatory center?

A
  • Muscular activity
  • Neonatal animals
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5
Q

Define hyperthermia?
Define fever?

A

Hyperthermia: elevation in core body temperature above the normal range as a result of heat being produced or stored in the body at a rate greater than it is lost.

Fever: hyperthermia where the set point in the anterior hypothalamus has been reset to a higher temperature.

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6
Q

Name a few mechanisms of heat gain or loss within the hypothalamus

A

Heat gain mechanisms:
- Increased production: catecholamine, thyroxine, shivering

  • Decreased loss: vasoconstriction piloerection, postural changes, seeking warm environment

Heat loss mechanisms:
- Panting, vasodilation, postural changs, seeking cool environments, perspiration, grooming

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7
Q

Describe the pathophysiology of fever

A

Exogenous pyrogens (ex: infectious agents, antigen-antibody complexes, tissue inflammation and necrosis, pharmacologic agents) –> activation of immune cells (macrophages, T & B cells) –> release of cytokines (endogenous pyrogens such as IL-1, IL-6, TNF-alpha) can also be produced directly by neoplastic cells –> reach the hypothalamus via circulation –> release of prostaglandins (PGE2) –> increased set point –> increased fever

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8
Q

What are the 3 main endogenous pyrogens and 3 other endogenous pyrogens

A

3 main:
- IL-6
- IL-1
- TNF-alpha

Others:
- IFN-gamma
- IFN-alpha
- IFN-beta
- TNF-beta
- IL-8
- Macrophage inflammatory protein 1

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9
Q

What are the 4 mechanisms of heat loss in the body

A
  1. Radiation: electromagnetic heat exchange between objects in the environment.
  2. Conduction: between the body and environmental objects that are in direct contact with the skin (relative temperatures and gradients)
  3. Convection: movement of fluid, water or air over the surface of the body.
  4. Evaporation: disruption of heat by the energy required to convert the material from a liquid to a gas
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10
Q

In active cooling, what mechanism of heat loss can be affected by applying very cold water to the patient?

A

Cold water can cause peripheral vasoconstriction, inhibiting radiant heat loss.

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11
Q

What is the hyperpyrexic syndrome?

A

Associated with exercise in a hot and humid environment –> evaporative cooling via panting is minimal + vasodilation to skeletal muscles with simultaneous vasoconstriction of the skin = compromised peripheral heat loss

Leads to weakness and collapse –> if temp > 41C, immediate cooling / if temp > 41.6C, may lead to permanent organ damage

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12
Q

Name a few pathologic and pharmacologic causes of hyperthermia

A
  • Hypothalamic lesion
  • Malignant hyperthermia - disturbs calcium metabolism, leads to myopathy with increased heat production (dantrolene is a specific and effective therapy)
  • Hyperthyroidism
  • Pheochromocytoma
  • Opioids
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13
Q

What are benefits and detriments of fever?

A

Benefits:
- Decreases ability of bacteria to use iron (which they need to live and replicate)
- Viruses are heat sensitive and cannot replicate in warm environments
- Increases leukocyte function

Detriments:
- Increases cellular O2 consumption which may exceed delivery
- Increases tissue metabolism and water requirements
- Suppression of appetite center in the hypothalamus
- Deleterious in TBI
- Heat stroke/malignant hyperthermia –> Rhabdomyolysis, myoglobinemia, hyperK, hypoCa

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14
Q

Name nonspecific therapies for the febrile patient.

A
  • NSAIDs - inhibit prostaglandin synthesis
  • Total body cooling –> counter productive in true febrile patients as even with cooling, the hypothalamic set point remains high which will lead to increased metabolic rate and O2 consumption
  • Glucocorticoids - block acute-phase response - reserved for when cause is non infectious
  • Phenothiazine - depresses thermoregulation and causes vasodilation
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15
Q

How are neutrophils activated?

A
  • Once migrated into the interstitial space, the PRRs (pattern recognition receptors) on their cellular membrane bonds to PAMPs (pathogen associated molecular patterns) on the cell wall of pathogens
  • When PRRs bind to DAMPs
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16
Q

How do neutrophils kill pathogens (3)?

A
  1. Degranulation - release of destructive peptides and proteases
  2. Assembly of s ROS generator (NADPH oxidase complex) on the membrane of a phagosome –> produces an oxidative burst when activated by microorganisms
  3. Formation of NETs (neutrophil extracellular traps)
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17
Q

What cytokine is responsible for the production of neutrophils?

A

G-CSF (granulocyte colony stimulating factor)

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18
Q

Name causes of granulocyte progenitor cell depletion in animals with febrile neutropenia.

A
  • Infectious diseases
    –> Parvovirus - neutrophils are affected early because hey have the shortest half life
    –> Erlichia canis
    –> FIV/FeLV - increased risk of neutropenia
  • Medications, toxicants, radiation
    –> Idiosyncratic neutropenia with methimazole, some antiepileptics, antiinfective agents, phenylbutazone
    –> Chemotherapy
    –> Estrogens
  • Myelophthisis - bone marrow failure due to infiltration of abnormal tissue –> neoplastic cells - leukaemia, lymphoma, multiple myeloma, histolytic sarcoma
    –> collagen (myelofibrosis)
  • Cyclic hematopoiesis
    –> Genetic disorder - gray Collie syndrome
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19
Q

Describe the pathophysiology of myelodysplastic syndrome

A

Clonal expansion of a mutated hematopoietic cell –> these cells mature abnormally –> apoptosis before they are released from the BM

BM appears hyperplasticity with an abnormally high number of blasts , but insufficient cells in circulation

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20
Q

What are the 4 main mechanisms in the pathophysiology of sepsis?

A
  1. Loss of immunoregulatory homeostatic mechanisms (cytokines from interactions of PAMPs / DAMPs and PRRs, neuroinflammatory reflex)
  2. Dysregulation of inflammation and coagulation (upregulation of TF, downregulation of anti-coagulant pathways, downregulation of fibrinolysis, platelet activation)
  3. Loss of barrier function (endothelial, microcirculatory, mitochondrial) -> increased vascular permeability, further activation of coagulation and inflammation, cryptic shock and cytopathic hypoxia
  4. Loss of vasomotor tone (increased NO production by iNOS)
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21
Q

What is cryptic shock?

A

The disconnect between systemic hemodynamics and microcirculatory perfusion.

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22
Q

What microcirculatory alterations lead to decreased O2 extraction in tissues

A
  1. Microcirculatory dysfunction (from endothelial damage)
    - Heterogeneous microvascular blood flow
    - Decreased functional capillary density
    - Increased diffusional distance for O2
    (-> cryptic shock)
  2. Mitochondrial dysfunction
    - Dysfunctional electron transport chain (cytopathic hypoxia)
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23
Q

What is the term used to describe dysfunction of mitochondria in sepsis?

A

Cytopathic hypoxia

Superoxides from neutrophils + NO combine to form peroxynitrite -> “mitochondrial permeability transition (MPT)” -> loss of H+ gradient -> inhibition of mitochondrial respiration and synthesis of ATP

Cytopathic hypoxia may lead to cellular dysfunction up to cell death

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24
Q

Describe how the interactions between PAMPs and PRRs contributes to development of sepsis

A

Part of the innate response (min to hours)

PRRs such as toll-like receptors recognize PAMPs such as lipopolysaccharide (found on gram negative cell wall) –> trigger a cascade leading to activation of NF-kB –> production of proinflammatory cytokines (TNF-alpha, IL-1, NO, ROS) + anti-inflammatory cytokines

DAMPs are released as well form tissue injury and recognized by + further activate PRRs

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25
Describe the adaptive response in sepsis
Occurs in days post-infection - B-lymphocytes mature into plasma cells that produce organism specific antibodies - Antibodies attach to the antigen and mark for destruction - Other lymphocytes migrate to thymus and mature into helper, killer or regulatory T cells - Type 1 helper T cell secretes proinflammatory cytokines - Type 2 secretes anti-inflammatory cytokines - Dendritic cells are for communication between innate and adaptive systems (present antigen to T cells)
26
How can neutrophils directly lead to endothelial injury?
- Phagocytosis of pathogen leads to controlled production of ROS --> in sepsis ROS production may be uncontrolled --> more widespread inflammation and increased microvascular permeability - Neutrophils also fuse granules containing protease enzymes to kill pathogens --> Excessive inflammation can lead to widespread release of protease = more endothelial damage
27
What is the most potent stimulus for production of TNF-alpha in sepsis?
Lipopoylsaccharide (PAMP)
28
Name examples of PAMPs and DAMPs
PAMPs: - Lipopolysaccharide (Gram -) - Lipotechoic acid (Gram +) - Peptidoglycan (Gram +) - Flagellin - CpG DNA - RNA DAMPs: - High mobility group box 1 (HMGB1) - Heat shock proteins - Histones - ATP - Mitochondrial DNA
29
What is the difference between surface TLRs and endosomal TLRs and name examples.
Surface TLRs recognize extracellular bacteria (bacterial lipids, flagellin, etc) whereas endosomal TLRs (found in the cytoplasm) detect intracellular bacteria (viral RNA, CpG DNA, mycoplasma) and viral organisms Surface TLRs: - TLR-1, 2, 4, 5, 6 Endosomal TLRs: - TLR-3, 7, 8, 9
30
Describe the intracellular cascade following TLR detection of PAMP.
- TLRs recognize PAMPs - Intracellular domain of TLR is activated - Recruitment of adapter proteins (ex: MyD88, TRAM, TRIF) - Recruitment and activation of protein kinases (ex: IRAK, Map kinase, IkB kinase) - Activation of transcription factors (ex: NF-kB = nuclear factor-kappa B, active AP-1) - Gene transcription - upregulation of expression of inflammatory cytokines, chemokines, endothelial adhesion molecules
31
What are the 2 different pathways by which LPS binding to TLR 4 can lead to cytokine production
- MyD88-dependent pathway -> activation of IRAK -> MAP kinase cascade (transcription factor AP-1) and IkB kinase cascade (transcription factor NF-kB) - TRAM / TRIF pathway (less important)
32
What are the different PAMP/TLR combinations?
- TLR-1:TLR-2 (heterodimer) --> Bacterial triacylated lipopeptides - TLR-2 --> Gram + bacteria (peptoglycan, lipoprotein, lipotechoic acid), viral hemagglutinin - TLR-4 (+ CD14)--> Gram - bacteria (LPS) - TLR-5 --> bacterial flagellin - TLR-2:TLR-6 (heterodimer) --> bacterial diacylated lipopeptides and lipotechoic acid
33
What's are the 4 mechanisms of functions of cytokines?
- Pleiotropism - Redundancy - Synergy - Antagonism
34
What does CARS stand for in sepsis?
Compensatory anti-inflammatory response syndrome *can lead to immunoparalysis
35
Name mechanisms of increased vascular permeability and microcirculatory derangements in sepsis
- Endothelial dysfunction - Damage to endothelial glycocalyx - Changes to RBCs - Leukocyte activation - Microthrombosis - Loss of vascular smooth muscle autoregulation
36
Describe mechanisms that promote the pro coagulable state seen with sepsis
- Upregulation of tissue factor --> combines with factor VIIa to initiate coagulation cascade - Downregulation of antithrombin, tissue factor pathway inhibitor (TFPI), tissue plasminogen activator (TPA) + increased plasminogen activator inhibitor (PAI-I) --> inhibition of natural anticoagulant and antifibrinolytic processes - Damaged EG --> pro coagulable state + release of vWF - Inhibition of protein C/S pathway - reduction of anticoagulant and antiinflammatory effects - Platelets: activated platelets recruit neutrophils to site of inflammation, secrete ADP, vWF, thromboxane A2, growth factors, serotonin and coagulation factors, trigger endotheial cell release of unusually large vWF multimers, further recruit platelets and contribute to microthrombi --> endothelial cell damage and macrothrombosis. Consumption leads to thrombocytopenia (common finding in sepsis)
37
What can lead to EG injury in sepsis?
- Inflammation --> activation of metalloprotease, heparinase, hyaluronidase by cytokines and ROS - Overaggressive fluid resuscitation also contributes to glycocalyx degradation - Microthrombosis
38
Name a few hematologic and biochemical abnormalities that can be seen in sepsis.
Hematologic: - Leukocytosis/leukopenia - Bands - Toxic neutrophils - Thrombocytopenia - Coat abnormalities Biochemical: - Hyper/hypoglycemia - Hypoalbuminemia - Hyperbilirubinemia - Ionized hypocalcemia - Pre-renal azotemia - Metabolic acidosis
39
What defines circulatory failure in sepsis?
SBP < 90 and MAP < 60 or decrease in SBP greater that 40mmHg from baseline despite adequate volume
40
What is one negative prognostic factor in dogs and in cats with sepsis?
Dogs: failure to normalize blood pressure with fluid resuscitation in the ER Cats: presence of cardiovascular instability upon presentation
41
What is the most commonly reported clinical manifestation of CIRCI?
Pressor-resistant hypotension --> glucocorticoids influence adrenergic receptor function * complete adrenal failure is an uncommon manifestation of CIRCI
42
Name some homeostatic functions of cortisol
- Regulation of carbohydrate, lipid and protein metabolism - Immune system modulation - Ensuring proper production of catecholamines - Ensuring function of adrenergic receptors - Stabilizing cell membranes
43
Describe the normal physiology of cortisol production
Hypothalamic-pituitary-adrenal axis (HPA) Hypothalamus produces CRH (corticotropin-releasing hormone) --> in synergy with vasopressin, stimulates anterior hypothalamus to release ACTH --> ACTH stimulates zona fasiculata & reticularis of adrenal gland to produce + release cortisol Cortisol has negative feedback on hypothalamic and pituitary release of CRH and ACTH Free cortisol is biologically active, but most is bound to CBG (corticosteroid binding globulin) and albumin
44
What are some mechanisms that can explain CIRCI?
- Direct trauma, infarction, hemorrhage, or cytokines may impair HPA axis function and decrease circulating cortisol - Target tissues may be cortisol resistant in sepsis: alteration in glucocorticoid receptors (GR) -> decreased binding of cortisol to GR, decreased translocation to nucleus, altered cortisol-dependent gene transcription - Increased free and total cortisol in the face of low ACTH: reduced hepatic synthesis of carrier proteins (= corticosteroid-binding globulin CBG) from inflammation, destruction of CBG by neutrophils, impaired cortisol metabolism by liver and kidney
45
What are the early pro-inflammatory cytokines? Late pro-inflammatory cytokines?
Early (minutes): - TNF-alpha - IL-1-beta - IL-6 --> recruit leukocytes at site of infection and activate leukocyte to kill pathogen + positive feedback loop Late: - HMGB-1 (DAMP)
46
What intrinsic regulators cause vasodilation in sepsis?
1. NO-mediated: LPS and inflammatory cytokines (IL-1, TNF) --> production of inducible nitric oxide synthase (iNOS) --> iNOS aids in conversion of L-arginine to L-citrulline --> produces NO --> production of cGMP in smooth muscle --> cGMP-mediated vasodilation --> distributive shock + bradykinin and thrombin increase activity of eNOS (endothelial NO synthase - constitutive) 2. Prostacyclin-mediated: PAMPs and inflammatory cytokines -> induction of COX-2 -> synthesis of PGI2 (prostacyclin) -> cAMP-mediated vasodilation 3. Hydrogen-sulphide-mediated: Hydrogen sulphide synthesized from L-cysteine -> inhibits cytochrome C oxidase + activates K+ ATP channels + inhibits endothelial ACE -> vasodilation 4. Metabolite-mediated: Hypoxia, reduced pH, increased lactate -> activation of K channels -> cell hyperpolarization -> vasodilation
47
What extrinsic regulator pathways contribute to vasodilation in sepsis
1. Catecholamine resistance (decreased expression of alpha1 receptors) 2. Glucocorticoid insufficiency / resistance (CIRCI) -> contributes to catecholamine resistance + causes angiotensin II resistance 3. Decreased vasopressin levels
48
What is the role of the complement in sepsis?
Recruitment and activation of leukocytes --> C5a, C3a are the most inflammatory of the competent components
49
Name 2 anti-inflammatory cytokines? What are other anti-inflammatory components?
- IL- 10 - TGF-beta Other: - Suppressors of cytokine signalling - Heat shock proteins (DAMP) - Phosphatase - Cortisol - microRNAs
50
How can natriuretic peptides affect endothelial glycocalyx in sepsis?
Increased cardiac filling pressures with agressive fluid resuscitation --> release of natriuretic peptides Natriuretic peptides clean syndecan-1 and hyaluronic acid off glycocalyx Natriuretic peptides also inhibit lymphatic drainage
51
What is the main cardiac change seen with sepsis?
LV diastolic dysfunction - Biventricular dilation can be seen, decreased ejection fraction, hypotension despite fluid therapy and decreased response to catecholamines - Decreased myocardial contractility from endotoxins and cytokines..
52
Prognosis of CIRCI?
Prognosis of return to normal HPA axis function following an episode of CIRCI is very good in patients that recover from the acute or critical illness
53
Name 3 antimicrobial determinants of pathogen clearance in sepsis
- Early antimicrobial therapy - Using bactericidal drugs, optimizing pharmacokinetics, combination therapy - Prompt and adequate source control
54
Define MODS
Presence of altered organ function in an acutely ill patient such that homeostasis can not be maintained without intervention --> Sequelae of sepsis, trauma, neoplasia or other cause of SIRS --> Associated with poor outcome
55
What is the cellular hibernation-like state in sepsis?
Cellular downregulation during inflammation, which transient and can return when animal recovers. If occurs for too longs, irreversible organ damage may result
56
One-hit, 2-hit and sustained-hit model in MODS
- One-hit model: develops as a result of a massive initial insult (ex: sepsis) - Two-hot model: priming insult followed by a subsequent insult (even small) enhancing inflammation and immune dysfunction - Sustained-hit model: continuous insult - causes initial insult and sustains the dysfunction (ex: ventilator associated pneumonia)
57
What are mechanisms of MODS?
- Cell tissue hypoxia - Induction of cellular apoptosis - Translocation of microbes from GI tract - Immune system dysregulation (imbalance between pro and anti-inflammatory mechanisms) - Mitochondrial dysfunction
58
Briefly describe mechanisms/manifestation of hepatic dysfunction in MODS
Hepatic dysfunction - Primary stage = septic shock --> hepatic hypoperfusion --> decreased protein synthesis, lactate clearance, gluconeogenesis, glycogenolysis --> hypoglycemia and coagulopathy - Secondary stage = Kupffer cell activation --> proinflammatory cytokines, chemokines, ROS and NO --> further liver damage and dysfunction - Clinically: hyperbilirubinemia in the absence of pre-existing liver disease - Hepatic dysfunction is an inconsistent predictor of mortality
59
What is a common manifestation of respiratory dysfunction in MODS?
ARDS
60
What is a mechanism of GI dysfunction in MODS?
Alteration in normal GI flora and disruption of the barrier --> translocation
61
What body system affected by MODS is a negative prognostic indicator?
Coagulation and presence of DIC * in people, number of dysfunctional organ systems correlates with mortality
62
What is particular to renal dysfunction that is specific to MODS in sepsis?
Apoptosis caused by cytokines and endotoxin. During sepsis renal blood flow is adequate, therefore no necrosis (as seen with other AKIs) During sepsis induced AKI, efferent arteriole dilates more than afferent arteriole --> increased renal blood flow, and decreased GFR
63
Briefly describe mechanisms/manifestation of CNS dysfunction in MODS
Sepsis induced encephalopathy - deterioration of mental status, not completely understood Inflammatory mediators stimulate afferent fibers of vagus nerve --> activation of cerebral endothelial cells --> breakdown of BBB
64
3 risk factors of developing sepsis in dogs following chemotherapy
- Lower body weight - Dx of lymphoma - Administration of doxo or vinc
65
How to NSAIDS and steroids reduce fever?
NSAIDs: inhibition of cyclooxygenase -->inhibition of production of prostaglandins --> decrease the set- point temperature Steroids: block release of arachidonic acid from brain phospholipids --> prevent production of prostaglandins
66
In dogs with septic shock, what organs most commonly have dysfunction (based on 2021 JVECC paper: Clinical features and outcome of septic shock in dogs: 37 Cases (2008-2015))
Cardiovascular > respiratory > hematologic (and coag) > renal > hepatic (but seems to change in every study...)
67
What causes hyperlactatemia in sepsis
- Increased glycolysis stimulated by catecholamines - Skeletal muscle Na/K ATPase stimulation by catecholamines - Mitochondrial dysfunction -Increased hepatic lactate production - Decreased hepatic lactate extraction - Impaired tissue O2 extraction - Capillary shunting
68
What are possible causes of decreased cardiac contractility in sepsis
- Oxidative injury to myocardial cells - NO -> downregulation of myocardial beta2-adrenergic receptors and decreased cytosolic Ca - Mitochondrial damage from cytokines and endotoxin - Adherence of macrophages and neutrophils to cardiomyocytes due to cytokines -> affected calcium release - C5a affecting intracellular calcium homeostasis in cardiomyocytes
69
List a few mechanisms contributing to immune paralysis in the late stages of sepsis
- Secretion of anti-inflammatory cytokines - Macrophage deactivation with decreased antigen-presenting capabilities - Apoptosis of B cells, T cells, dendritic cells - T cells express Programmed cell death-1 (PD-1) on their surface of T cells, neutrophils and macrophages have increased expression of PD-1 ligand - Increased Treg cells
70
Describe mechanisms of AKI in sepsis
- Ischemia from hypoperfusion (macrohemodynamic failure) likely to have little role - Micro-thrombi due to activation of coagulation - Oxidative damage by ROS - Disruption of tight junctions due to inflammation -> back-leakage of fluid + formation of casts and tubular obstruction (but likely not the main cause because no tubular damage seen on histopath -> cells likely suffer sublethal changes)
71
What hemoglobin change can be noted in dogs with sepsis
Methemoglobinemia in ~20% of dogs due to increased NO and decreased activity of methemoglobin-reducing enzymes + overwhelmed endogenous anti-oxidants
72
What is the difference between a cytokine and a chemokine?
Cytokines are proteins responsible for cell signalling - released by cells Chemokines are a type of cytokine that induces chemotaxis
73
Why is persistent hyperglycemia deleterious to the septic patient?
- Associated with increased risk of acquiring new infections - Impaired granulocyte chemotaxis - Decreased neutrophil function - Pro-oxidant and pro-inflammatory --> procoagulant - Increased NF-kb binding activity - ROS generation - Increased NO expression --> endotheliopathy - Endothelial glycocalyx injury
Sepsis/SIRS/MODS
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