By Dr Rubia Khan ST1, Histopathology Derriford Hospital
� 60% of lean body weight is water � 2/3 as intracellular � 1/3 as extracellular � (mostly as interstitial fluid ) � (only 5 % of total body water is plasma)
Edema � Accumulation of interstitial fluid within tissues � Based on location � 1. Hydrothorax � 2. Hydropericardium � 3. Hydroperitoneum (ascites) � 4. Anasarca
Types of edema � 1. Inflammatory edema – protein rich exudate that is result of
increased vascular permeability
� 2. Non-‐inflammatory edema – edema caused by increased
hydrostatic pressure or reduced plasma protein is typically protein poor fluid called transudate.
What causes edema � 1. Increased Hydrostatic Pressure � 2. Reduced Plasma Oncotic pressure � 3. lymphatic obstruction � 4. Sodium and water retention
Increased hydrosta5c pressure Deep vein thrombosis Congestive heart failure
� Constrictive pericarditis � Venous obstruction or compression Thrombosis External pressure (mass) Lower extremity inactivity with prolonged dependency
� Arteriolar dilatation Heat Neurohumoral dysregulation
Reduced Plasma Onco5c Pressure � Protein –losing glomerulopathies (nephrotic syndrome)
� Liver cirrhosis (ascites) � Malnutrition � Protein-‐losing gastroenteropathy
Lympha5c obstruc5on � Inflammation � Neoplastic � Postsurgical � Postirradiation
Sodium and water reten5on � Increased tubular resorption of sodium � Increased renin-‐angiotensin-‐aldosterone secretion
� Seen in poststreptococcal glomerulonephritis and acute renal failure
Morphology � Can be easily recognised grossly � Microscopically – it is appreciated as clearing and separation of the extracellular matrix and subtle cell swelling.
� Most commonly seen in -‐Subcutaneous tissue -‐Lungs -‐Brain Dependent edema Nephrotic syndrome
Clinical correla5on � Ranges from merely annoying to fatal � Subcutaneous edema used primarily to recognise underlying
cardiac or renal disease , if severe can impair wound healing or clearance of infection
� Pulmonary edema-‐ LVF, can also occur with renal failure, ARDS, and infection and inflammation of lungs. Can cause death by interfereing with normal ventilatory function.
� Brain edema is life threatening. When severe can cause herniation of brain. Compression of brain stem vascular supply
Shock Shock is characterised by systemic hypoperfusion of tissues; it can be caused by diminished cardiac output or by reduced effective circulating blood volume. Consequences are impaired tissue perfusion and cellular hypoxia.
Major types of shock
� Neurogenic shock � Anaphylactic shock
Pathogenesis of Sep5c Shock � Kills 20% of its victims � Number one cause of ICU deaths. � Increasing incidence due to 1. improved life support for critically ill patients
2. increase in invasive procedures 3. growing number of immunocompromised population
� The innate leukocytes include: Natural killer cells, mast cells, eosinophils, basophils; and the phagocytic cells including macrophages, neutrophils, and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection
Pathophysiology of Sep5c shock � Factors: � inflammatory mediators � Endothelial cell activation and injury � Metabolic abnormalities � Immune suppression � Organ dysfunction
1.Inflammatory mediators � innate immunity cells recognise a host of microbe derived susbtances containing so called pathogen associated molecular patterns( PAMPs).
� Activation of pathogen recognition receptors by PAMPs triggers the innate immune response that drive sepsis
� Upon activation , inflammatory cells produce � TNF (proinflammtory cytokines)
� IL-‐1 (proinflammtory cytokines)
� Cytokine like mediators HMGB-‐1 � Reactive oxygen species � Prostaglandins � Platelet activation factor
2.Endothelial cell ac5va5on and injury � Three main sequelae: � 1.thrombosis � 2.increased vascular permeability � 3.vasodilatation
Thrombosis � Pro inflammatory cytokines result in increased tissue factor production, at the same time dampening fibrinolysis by increased PAI expression.
� Production of other endothelial anticoagulant factors such as tissue factor pathway inhibitor, thrombomodulin and protein C is also diminished.
� Procoagulant tendency is further enhanced by decreased blood flow within small vessels, which produces stasis and diminished washout of activated coagulation factors.
Increased vascular permeability � Inflammatory cytokines loosen the endothelial cell tight junctions.
Vasodilata5on � Increase NO production and vasoactive inflammatory mediators leads to systemic relaxation of vascular smooth muscles, producing hypotension and further reduction in tissue perfusion.
3. Metabolic abnormali5es � Septic patients exhibit insulin resistance and hyperglycemia
� Cytokines and stress induced hormones drive gluconeogenesis.
� Pro-‐inflammatory cytokines suppress insulin release while simultaneously promoting insulin resistance in skeletal muscles and other tissues
� Hyperglycemia suppress neutrophil function-‐ decreases bactericidal activity-‐ increased adhesion molecule expression on endothelial cells.
4. Immune suppression � Hyper-‐inflammatory state initiated by sepsis can paradoxically lead to state of immunosuppression.
� Proposed mechanism include production of anti-‐inflammatory mediators and wide spread apoptosis of lymphocytes in the spleen and lymph nodes, cause of which is uncertain.
Organ dysfunc5on � High level of cytokines and secondary mediators can reduce myocardial contractility
� Increased vascular permeability and endothelial injury in pulmonary circulation leads to ARDS
� Ultimately, these factors conspire to cause multiorgan damage resulting in death.
Outcome � Difficult to predict � Standard care remains treatment with appropriate antibiotics , intensive insulin therapy , fluid resuscitation and physiological doses of corticosteroids to correct relative adrenal insufficiency
Stages of Shock � Stage 1: Initial � Stage 2: Non-‐progressive stage. (stage 1 & 2 are grouped
together)
� Stage 3: Progressive stage � Stage 4: Irreversible stage
Stage 1& 2 � Neurohumoral mechanisms : � 1.baroreceptor reflexes � 2.release of cathecholamines and ADH � 3. activation of renin-‐angiotensin-‐aldosterone axis � 4.generalised sympathetic stimulation
Net effect � 1. tachycardia � 2.peripheral vasoconstriction � 3.renal fluid conservation
Stage 3 � Persistent O2 deficit, causes activation of anaerobic glycolysis, increased production of lactic acid.
� Resultant lactic acidosis lowers the tissue pH, which blunts the vasomotor response resulting in arteriolar dilatation and pooling of blood in microcirculation.
� This reduces cardiac output further, endothelial cell injury due to hypoxia with subsequent DIC.
� Widespread tissue hypoxia, vital organs are affected and begins to fail.
Stage 4 � Widespread cell injury is reflected in lysosomal enzyme leakage.
� Myocardial contractile function worsens � Ischemic bowel may allow intestinal flora to enter circulation
� Ultimately death.