Septic shock pathogenesis, stages of shock and morphology of organs

Septic shock

Definition – Septic shock is defined as hypotension asoociated with severe sepsis and cannot be corrected by infusing fluids
Causes for Septic shock
- Overwhelming microbial infections (bacteria and fungi)
- Gram positive septicemia
- Gram negative bacteria
- Fungal sepsis
- Rarely protozoa or Rickettsiae

PATHOGENESIS

Major factors contributing to the pathophysiology include

Inflammatory mediators
Endothelial activation and injury
Induction of procoagulant state
Metabolic abnormalities
Organ dysfunction
Immune suppression

Inflammatory mediators

Microbial cell wall constituents (LPS) engage receptors on neutrophils, mononuclear inflammatory cells and endothelial cells leading to cellular activation
Activated cells produce inflammatory mediators like TNF, IL-1, IFN-γ, IL-12, IL-18, HMGB 1 (High mobility group box 1 protein), prostaglandins and PAF. These mediators activate endothelial cells which express adhesion molecules
They activate complement and coagulation cascade
Complement cascade is activated by microbial components – results in production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a) and opsonins (C3b). All these contribute to proinflammatory state
Microbial components activate coagulation directly through factor XII and indirectly through altered endothelial function
Accompanying widespread activation of thrombin may further augment inflammation by triggering protease-activated receptors on inflammatory cells

Endothelial activation and injury

Endothelial cell activation and inflammatory mediators produce 3 major sequelae

Thrombosis
Increased vascular permeability
Vasodilation

Induction of procoagulant state

Pro inflammatory cytokine affects on endothelial cells
- Increase in tissue factor production
- Increased plasminogen activating inhibitors which prevent fibrinolysis
- Diminshed endothelial anticoagulant factors such as thrombomodulin and protein C

All these factors leads to formation of thrombi leading to Disseminated intravascular coagulation (DIC) which causes ischemic damage in various organs.
Later patient develops hemorrhage and bleeding due to the deficiency of platelets and coagulation factors

Metabolic abnormalities

Septic patients exhibit insulin resistance and hyperglycemia
Pro inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues by impairing surface expression of GLUT-4 a glucose transporter
Cytokines such as TNF and IL-1, stress induced hormones (glucagon, growth hormone and glycocorticoids) and catecholamines drive gluconeogenesis
Hyperglycemia leads decreased neutrophil function – which suppresses bactericidal activity and increased expression of adhesion molecules on endothelial cells
In sepsis – initially acute surge in glucocorticoid production followed by adrenal insufficiency
Adrenal insufficiency – due to depression in sympathetic capacity of intact gland or due to adrenal necrosis because of DIC (Waterhouse Friderichsen syndrome)
Hypoxia leads to metabolic acidosis and electrolyte imbalance due to sodium pump failure

Immune suppression

Hyper inflammatory state initiated by sepsis can activate counter regulatory immunosuppressive mechanisms
Shift from pro inflammatory to anti-inflammatory cytokine production (IL-10, IL-1 receptor antagonists etc)
Lymphocyte apoptosis and induction of cellular ageing

Organ dysfunction

Systemic hypotension, interstitial edema and small vessel thrombosis leads to decreased delivery of oxygen and nutrients to the tissues which produces alterations in cellular metabolism
High levels of cytokines and secondary mediators diminish myocardial contractility, cardiac output, endothelial injury and increased vascular permeability
These factors lead to multiple organ failure

Severity and outcome of septic shock depends upon

Extent and virulence of the infection
The immune status of the host
The presence of other co-morbid conditions
Levels of mediator production

Shock is progressive disorder that if uncorrected leads to death

Shock evolves through 3 phases

Initial non-progressive phase
Progressive phase
Irreversible stage

Initial non-progressive phase

Compensatory mechanism to maintain the homeostasis so that blood supply to vital organs is maintained
By neuro humoral mechanism which maintains blood pressure and cardiac output
Widespread vasoconstriction of vessels except coronary and cerebral vessels
Fluid conservation by kidney
Tachycardia

Progressive phase

As the stage advances there is failure of compensatory mechanism, dilatation of arterioles, veinules and capillary bed
Because of this fluid leaks out of capillaries into interstitium and there is sludging of blood
This reduces the tissue perfusion leading to hypoxia
Initially body tissue except brain and heart suffers from hypoxia

IRREVERSIBLE PHASE

Cellular injury and tissue injury is so severe that condition does not revert back to normal even after correcting hemodynamic defects
Hypoxic and ischemic cell injury – causes leakage of lysosomal enzymes which further aggravates condition
Myocardial infarction and synthesis of NO further worsens condition
Intestinal ischemia causes microbes from intestinal flora to enter the circulation which produces superimposed bacteremic shock
Acute tubular necrosis occurs in kidney

Signs and symptoms in different phases

Compensated phase

15 to 25% of fluid loss from vessels and there are subtle signs of shock
Mean arterial pressure will be less than 10-15mm Hg from the baseline
Increased Renin and Anti-diuretic hormone secretion
Vasoconstriction
Increased heart rate
Decreased pH

Intermediate phase

25 to 35% of fluid loss from vessels and classical signs of shock appears
Mean arterial pressure is less than 20mmHg from Base line
Tissue hypoxia develops
Decreased urine output (oliguria)
Weak rapid pulse
Decreased pH

Irreversible phase

>35% of fluid loss from vessels, body cells die to hypoxia and vital signs come to bottom
Anuria
Excessive organ or tissue damage
Multi organ failure
Decreased pH

Morphology

Changes manifest mainly in brain, heart, lungs, kidney, adrenals and GIT
Adrenals – there is cortical cell lipid depletion reflecting relatively inactive vacuolated cells to metabolically active cells that utilize stored lipids for the synthesis of steroids
Heart – due to hypoxia and fall in cardiac output – myocardial infarction
Brain – cerebral ischemia develops leading to altered state of consciousness
Liver – congestion and centrilobular necrosis
GIT –erosions of gastric mucosa and Diffuse ischemic necrosis of intestine
Lungs
- congestion and edema develops leading later to formation of hyaline membrane and alveolar collapse.
- If patient survives organization and fibrosis occurs leading to emphysema and bronchiectasis
Kidney
- fall in the BP leads to reduction in glomerular filtrate which further produces uremia due to retention of waste products
- Due to tubular ischemia, tubular necrosis develops which leads to anuria further leading to severe progressive uremia

Septic shock

Definition – Septic shock is defined as hypotension asoociated with severe sepsis and cannot be corrected by infusing fluids

Causes for Septic shock

Overwhelming microbial infections (bacteria and fungi)

Gram positive septicemia

Gram negative bacteria

Fungal sepsis

Rarely protozoa or Rickettsiae

PATHOGENESIS

Major factors contributing to the pathophysiology include

Inflammatory mediators

Endothelial activation and injury

Induction of procoagulant state

Metabolic abnormalities

Organ dysfunction

Immune suppression

Inflammatory mediators

Microbial cell wall constituents (LPS) engage receptors on neutrophils, mononuclear inflammatory cells and endothelial cells leading to cellular activation

Activated cells produce inflammatory mediators like TNF, IL-1, IFN-γ, IL-12, IL-18, HMGB 1 (High mobility group box 1 protein), prostaglandins and PAF. These mediators activate endothelial cells which express adhesion molecules

They activate complement and coagulation cascade

Complement cascade is activated by microbial components – results in production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a) and opsonins (C3b). All these contribute to proinflammatory state

Microbial components activate coagulation directly through factor XII and indirectly through altered endothelial function

Accompanying widespread activation of thrombin may further augment inflammation by triggering protease-activated receptors on inflammatory cells

Endothelial activation and injury

Endothelial cell activation and inflammatory mediators produce 3 major sequelae

Thrombosis

Increased vascular permeability

Vasodilation

Induction of procoagulant state

Pro inflammatory cytokine affects on endothelial cells

Increase in tissue factor production

Increased plasminogen activating inhibitors which prevent fibrinolysis

Diminshed endothelial anticoagulant factors such as thrombomodulin and protein C

All these factors leads to formation of thrombi leading to Disseminated intravascular coagulation (DIC) which causes ischemic damage in various organs.

Later patient develops hemorrhage and bleeding due to the deficiency of platelets and coagulation factors

Metabolic abnormalities

Septic patients exhibit insulin resistance and hyperglycemia

Pro inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in the liver and other tissues by impairing surface expression of GLUT-4 a glucose transporter

Cytokines such as TNF and IL-1, stress induced hormones (glucagon, growth hormone and glycocorticoids) and catecholamines drive gluconeogenesis

Hyperglycemia leads decreased neutrophil function – which suppresses bactericidal activity and increased expression of adhesion molecules on endothelial cells

In sepsis – initially acute surge in glucocorticoid production followed by adrenal insufficiency

Adrenal insufficiency – due to depression in sympathetic capacity of intact gland or due to adrenal necrosis because of DIC (Waterhouse Friderichsen syndrome)

Hypoxia leads to metabolic acidosis and electrolyte imbalance due to sodium pump failure

Immune suppression

Hyper inflammatory state initiated by sepsis can activate counter regulatory immunosuppressive mechanisms

Shift from pro inflammatory to anti-inflammatory cytokine production (IL-10, IL-1 receptor antagonists etc)

Lymphocyte apoptosis and induction of cellular ageing

Organ dysfunction

Systemic hypotension, interstitial edema and small vessel thrombosis leads to decreased delivery of oxygen and nutrients to the tissues which produces alterations in cellular metabolism

High levels of cytokines and secondary mediators diminish myocardial contractility, cardiac output, endothelial injury and increased vascular permeability

These factors lead to multiple organ failure

Severity and outcome of septic shock depends upon

Extent and virulence of the infection

The immune status of the host

The presence of other co-morbid conditions

Levels of mediator production

Shock is progressive disorder that if uncorrected leads to death

Shock evolves through 3 phases

Progressive phase

Irreversible stage

Initial non-progressive phase

Compensatory mechanism to maintain the homeostasis so that blood supply to vital organs is maintained

By neuro humoral mechanism which maintains blood pressure and cardiac output

Widespread vasoconstriction of vessels except coronary and cerebral vessels

Fluid conservation by kidney

Tachycardia

Progressive phase

As the stage advances there is failure of compensatory mechanism, dilatation of arterioles, veinules and capillary bed

Because of this fluid leaks out of capillaries into interstitium and there is sludging of blood

This reduces the tissue perfusion leading to hypoxia

Initially body tissue except brain and heart suffers from hypoxia

IRREVERSIBLE PHASE

Cellular injury and tissue injury is so severe that condition does not revert back to normal even after correcting hemodynamic defects

Hypoxic and ischemic cell injury – causes leakage of lysosomal enzymes which further aggravates condition

Myocardial infarction and synthesis of NO further worsens condition

Intestinal ischemia causes microbes from intestinal flora to enter the circulation which produces superimposed bacteremic shock

Acute tubular necrosis occurs in kidney

Signs and symptoms in different phases

Compensated phase

15 to 25% of fluid loss from vessels and there are subtle signs of shock