GP 30 - Hemodynamic Disorders 3

Question 1

List and briefly describe the stages of shock.

Answer 1

1. Non-progressive - compensatory mechanisms are able to maintain MAP and perfusion to the vital organs
2. Progressive - compensatory mechanisms are now only able to maintain just enough MAP and perfusion to prevent cell injury/death. Cells begin anaerobic glycolysis
3. Irreversible (aka - decompensation) - severe and widespread cell and tissue injury occurs due to an almost complete lack of perfusion

Question 2

List the major compensatory mechanisms that maintain MAP and tissue perfusion during the Non-progressive stage of shock. What are the cardinal features of this stage?

Answer 2

Compensatory Mechanisms - baroreceptors (increased HR), release of catecholamines, RAA axis, ADH release, and generalized sympathetic stimulation causing increased HR, peripheral vasoconstriction, and renal conservation of fluid.

Cardinal Features - cool/pale skine (skin will be flushed/warm in septic shock) and possibly pre-renal uremia (increased urea in the blood) as a result of poor kidney perfusion.

Question 3

List the major events occuring during the progressive stage of shock.

Answer 3

• Imbalance between circulation and metabolic needs
• Anaerobic metabolism starts, causing excess lactic acid build up and low pH
• Low pH blunts the vasomotor response (symapthetic innervation doesn’t have as strong an effect on vasoconstriction) leading to ateriolar dilation
• Blood pools in microcirculation
• Reduced CO
• Anoxic endothelial cell injury causing DIC
• Descreased blood flow to brain

Question 4

What are the cardinal features of the progressive stage of shock?

Answer 4

• Acidemia (increased lactic acid)
• DIC
• Confusion (reduced blood flow to brain)
• Urine output decreases (low GFR)

Question 5

What are the cardinal features of irreversible shock?

Answer 5

• All symptoms from previous stages worsen
• Coma
• Severe widespread cell and tissue injury causing leakage of lysosomal enzymes which aggravates the shock
• Failur of multiple organ systems
• Ischemic bowel allows entry of bacteria into the circulation causing endotoxic shock
• Low survivability rate even if hemodynamics are corrected

Question 6

What is this an image of? Note the important feature(s).

Answer 6

This is the heart from someone who died of septic shock. Along the line of closure, there are solid masses called vegitations, which are essentially colonies of bacteria.

Question 7

What is the number one cause of death in an ICU? What is this disease’s mortality rate? What are the major effects of this disease?

Answer 7

• Septic Shock (20% mortality rate)
  
  • Systemic arterial/venous dilation (tissue hypoperfusion)
  • Widespread activation of endothelial cells eventually leading to DIC and consumptive coagulopathy
  • Multiorgan dysfunction

Question 8

What are the most common causes of septic shock?

Answer 8

• Used to be Gram Negative infection (hence endotoxic shock) but since the proliferation of Abxs, Gram positive infections are the most common cause
• Other bacterial and fungal infections
• Super Antigens (bacterial proteins that overstimulate T Cell activation). This type of septic shock is called Toxic Shock Syndrome

Question 9

Can an infection remain localized (without any detectable spread through blood stream) and still cause septic shock?

Answer 9

Yes

Question 10

Give the general overview of how an infection leads to septic shock.

Answer 10

1. Microbes release PAMPs (pathogen associated molecular patterns) which cause endothelial activation either directly or indirectly (by activating inflammatory cells & the complement system)
2. Widespread endothelial activation leads to a massive release of inflammatory cytokines (SIRS - systemic inflammatory response syndrome)
3. Increased vasodilation, permeability, and DIC all lead to decreases perfusion, tissue ischemia, and multiorgan failure

Question 11

What are anaphylotoxins and what do they do?

Answer 11

Fragments (C3a, C4a and C5a) that are produced as part of the activation of the complement system. They cause smooth muscle contraction, vasodilation, histamine release from mast cells, and enhanced vascular permeability.

Question 12

What are opsonins and what do they do?

Answer 12

An opsonin is any molecule that enhances phagocytosis by marking an antigen for an immune response or marking dead cells for recycling

Question 13

What does “endothelial cell activation” mean? How do PAMPs indirectly activate enothelial cells?

Answer 13

Endothelial cells normally release both prothrombotic and anti-thrombotic mediators. Endothelial activation means they have shifted towards releasing much more prothrombotic mediators.

PAMPs indirectly activate endothelial cells in two primary ways:

• Neutrophil/Monocyte activation, causing them to release TNF, IL-1, HMGB1, prostaglandins, and platelet activating factors
• Complement system activation causing the increased production of anaphylotoxins (C3a, C5a), chemotaxic fragments (C5a), and opsonins (C3b).

Question 14

How does septic shock cause edema?

Answer 14

The pro-inflammatory cytokines lossen the endothelial tight junctions by displacing the adhesion molecule VE-Cadherin. This causes leaky vessel walls.

Question 15

How does septic shock cause hypotension/vasodilation?

Answer 15

C3a, C5a, and PAF (platelet activating factor) are vasoactive inflammatory mediators that cause the endothelial cells to increase production of NO.

Question 16

What are the metabolic abnormalities caused by septic shock that we need to know?

Answer 16

• Hyperglycemia
  
  • Increased gluconeogenesis - increased TNF and IL-1 release cause the release of stress hormones (glucagon, GH, glucocorticoids) and catecholalmines which upregulate gluconeogenesis
  • The pro-inflammatory cytokines cause insulin resistance and suppress insulin release
• The hyperglycemia both suppresses the phagoctic activity of PMNs and increases the expression of adhesion molecules on endothelial cells (contributes to prothrombotic state)
• After the initial surge in glucocorticoid release, there will be a depression due to DIC causing a blockage of the arteries to the adrenal glands
• Lactic Acidosis

Question 17

What is Waterhouse-Friderichsen Syndrome? When is it usually seen?

Answer 17

Adrenal necrosis caused by DIC

Usually seen in septic shock. It contributes to the glucocorticoid depression seen in septic shock.

Question 18

How does septic shock cause immunosuppression?

Answer 18

• The initial hyper-inflammatory state will lead to the production of anti-inflammatory mediators, TNF & IL1 receptor antagonists.
• Septic shock also causes lymphocyte apoptosis in lymph nodes and spleen

Question 19

List the major organ system dysfunctions caused by septic shock.

Answer 19

• High levels of cytokines and secondary mediators reduce myocardial contractility, reducing cardiac output
• Increased vascular permeability and endothelial injury in the lungs causes Acute Respiratory Distress Syndrome (ARDS)
• Ultimately, multi-organ failure occurs because of the hypotension, increased vascular permeability, tissue edema, and DIC all causing ischemia/hypoxia

Question 20

What is the usual treatment plan for septic shock?

Answer 20

• Antibiotics
• Intensive insulin therapy
• Fluid Replacement
• Physiologic doses of corticosteroids
• Experimental drugs to restore endothelial cell integrity

Question 21

What are the morphological changes typically seen in the brain during septic shock?

Answer 21

• Ischemic Encephalopathies
  
  • Edema
  • Mottled discoloration in grey matter
  • Grey-White junction blurring
  • Neuronal necrosis, especially in the pyramidal cells of the hippocampus and the purkinje cell of the cerebellum
  • Laminar cortical necrosis
  • Watershed infarcts
  • Hemorrhages

Question 22

What is a watershed infarct? When are these common? How does this type of infarct appear?

Answer 22

An infarct in a zone that receives dual blood supply.

A watershed zone recieves dual blood supply but from the terminal branches of two different arteries. Because of this, they are protected from infarcts due to blockage but are highly susceptible to infarct due to hypotension. The damaged tissue from a watershed infarct is typically wedge shaped.

Question 23

What is laminar necrosis? Where is it commonly seen? How does it appear?

Answer 23

Laminar necrosis is what occurs in the cortex of the brain when the short penetrating arteries are no longer able to perfuse their tissues. It appears as a line of necrotic tissue that follows along the path of the hypoperfused arteries.

Question 24

What key morphological change is seen in the heart during septic shock?

Answer 24

Contraction band necrosis which presents as hypereosinophilic bands.

Refer to image

Question 25

What is thrombosis? What is a thrombus?

Answer 25

Thrombosis - Inapropriate activation of normal hemostatic processes

Thrombus - a solid mass formed from circulating blood elements in the intact circulation

Question 26

List the primary causes of thrombosis?

Answer 26

Known as Virchow’s Triad

• Endothelial Injury (which can cause the other two causes)
• Abnormal blood flow (which can cause the other two causes)
• Hypercoagulability

Question 27

What is the primary cause of arterial thrombus formation?

Answer 27

Endothelial cell injury

Question 28

What are the major causes of endothelial cell injury so that it causes thrombus formation (not clot formation)?

Answer 28

• Stress induced by HTN
• Bacterial toxins in shock
• Hypercholesterolemia
• Homocystinuria
• Cigarette Smoking

Question 29

Describe why the loss of laminar blood flow can lead to thrombosis.

Answer 29

In normal laminar blood flow, the formed elements of the blood remain in the center of the flow and do not come into contact with the endothelium very frequently. When laminar flow is disrupted, either by stasis or turbulence, the platelets are allowed to come into contact with the endothelium, leading to local activation of coagulation factors.

The disruped flow also allows for the build-up platelets, fibrin, and activated clotting factors

Question 30

What are the primary causes of blood hypercoagulability?

Answer 30

• Hereditary
  
  • Factor V Leiden (most common)
  • Anti-thrombin III deficiency
  • Protein C deficiency
  • Protein S deficiency
• Acquired
  
  • Trousseau Syndrome - thrombogenic substances released from necrotic tumors
  • Cardiac Failure - anoxic damage to tissues causes the release of thrombogenic substances
  • Severe Trauma and Burns
  • Oral Contraceptives - increase production of clotting factors