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Edema

Hemodynamic Disorders • Excess accumulation of fluid in interstitial space or in serous cavity is called edema. • Types – Local edema Dr. Sadequel Islam Talukder – Generalized edema MBBS, M Phil (Pathology 1995, IPGMR)

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• Generalized edema • Local edema – Hepatic edema – Acute inflammatory edema – Cardiac edema – Allergic edema – Renal edema – Edema due to impaired venous return of leg following – Nutritional deficiency edema • Long journey – Pregnancy edema • Long period of standing – Myxedema – Lymphedema following lymphatic obstruction – Unexplained edema • e.g. Filariasis

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Elephantiasis • Clinical Types of Edema – Pitting edema • A non-pitting edema following lymphtaic – Non-pitting edema obstruction • Causes of edema/Pathophysiological Category • Accumulation of lymph in tissue – Increased hydrostatic pressure • Causes inflammation, fibrosis. – Decreased colloidal osmotic pressure • Fibrosis causes non-pitting edema. – Retention of salt and water – Lymphatic obstruction

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• Serous cavities – Peritoneal cavity - Excess accumulation of fluid is • All causes are found in hepatic edema called ascites. • Normally interstitial space and serous cavity – Pleural cavity - Excess accumulation of fluid is contains small amount of fluid. Excess amount called pleural effusion. of fluid cases edema. – Pericardial cavity - Excess accumulation of fluid is called pericardial effusion. – Synovial cavity - Excess accumulation of fluid is called synovial effusion.

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• Anasarca – Severe generalized edema is called • Fluid comes out from vessels due to anasarca. It is usually seen in nephrotic – Hydrostatic pressure in blood vessels syndrome. – Colloidal osmotic pressure (COP) in interstitial • Primary lymphedema – Edema due to fluid malformation of lymphatics. • Fluid enters in blood vessels due to • Starling postulate- Fluid movement between – Tissue tension extracellular space and blood vessels depends on balance of hydrostatic and osmotic – Colloidal osmotic pressure of plasma (80% COP is pressure. maintained by albumin)

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• Tissue where fluid easily accumulates Hepatic Edema – Eyelids – Scrotum – Ankle etc. • Edema in liver diseases is called hepatic • Tissue where fluid does not easily accumulates edema. – Palm – Cirrhosis – Sole – Hepatitis • Water moves – Carcinoma of liver etc. – From fluid of high hydrostatic pressure to low hydrostatic pressure – From low colloidal osmotic pressure to high colloidal osmotic pressure.

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• Pathogenesis of edema in cirrhosis • Hypoalbuminemia – Portal hypertension – Reduction of hepatic cell mass in cirrhosis • Contraction of liver due to extensive fibrosis in cirrhosis – Decreased albumin synthesis • Portal vein compression at porta hepatis. • Increased hydrostatic pressure in portal system. – Nutritional hypoalbuminemia • Transudation. – Transudation and generalized edema • Accumulation of fluid in peritoneal cavity and ascites. • Lymphatic obstruction at porta hepatis – Compression of porta hepatis – Impaired lymph drainage – Enhancement of ascites

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• Secondary hypertension Cardiac Edema – Reduction of hepatic cell mass – Delayed aldosterone metabolism. Thus half life of • Edema due to heart disease is called cardiac aldosterone is increased. edema. – Aldosterone acts upon renal tubules and • Example – Right-heart failure/Congestive absorption of sodium and water. cardiac failure (CCF) – Increased volume of blood – Increased hydrostatic pressure – Transudation and generalized edema.

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– Salt and water retention • Pathogenesis of cardiac edema • Impaired venous return • Decreased cardiac output – Increased hydrostatic pressure • Decreased renal blood flow -> Renin secretion from • Right heart failure causes impaired venous return juxtraglomerular system. • Increased blood volume in venous system. • Activation of renin angiotensin axis. • Increased hydrostatic pressure in blood. • Secretion of aldosterone -> absorption of sodium and • Transudation and generalized edema. water from renal tubules. • Increased blood volume. • Increased hydrostatic pressure in blood. • Transudation and generalized edema.

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Renal Edema • Pathogenesis of edema in nephritic syndrome • Edema following renal diseases is called renal – Proteinuria in nephrotic syndrome edema. • Mild to moderate proteinuria • Hypoalbuminemia • Renal diseases associated with edema • Decreased colloidal osmotic pressure – Nephritic syndrome (Syndrome in AGN) • Transudation and edema – Nephrotic syndrome

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• Pathogenesis of edema in nephrotic syndrome – Massive proteinuria or heavy proteinuria • Oligouria in nephritic syndrome • Hypoalbuminemia – Retention of salt and water in blood. • Decreased colloidal osmotic pressure in blood. – Increased volume of blood • Transudation and edema • Massive or heavy proteinuria – Increased hydrostatic pressure in blood » Passage of protein (albumin) > 3.5 gm in 24 hours. – Transudation and edema

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Clinical Importance of Edema Angioedema

• Cardiac edema – 1st appear in dependent part, • Edema in Type-I and Type-III hypersensitivity like, ankle. reaction. • Renal edema - 1st appear in face • Edema involves in dermis and subcutaneous • Hepatic edema - 1st appear in abdomen tissue. [ascites]

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Pulmonary Edema Hypoxia in pulmonary edema

• Accumulation of fluid in lung alveoli is called • Fluid in alveolar spaces cause scarcity of gas in pulmonary edema. alveoli. • Causes • Blood in interalveolar septal capillaries can not – Left ventricular failure obtain sufficient oxygen thus cellular hypoxia – Cerebral damage etc. throughout the body.

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Cerebral Edema • Example of vesogenic edema – edema in – Primary and metastatic tumors of brain • Brain is susceptible to edema , because of – Brain abscess – Little room to expand – of brain etc. – Absence of lymphatics to carry away any excess fluid that accumulates. • Cytotoxic edema • Types – Accumulation of fluid in cells of gray matter. – Vesogenic edema – loss of blood brain barrier – Example – edema in ischemic brain function results from damage of capillaries or newly formed capillaries that have not yet established barrier causes edema.

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• Interstitial edema Infarct and Infarction – Example – Edema in noncommunicating type hydrocephalus. Fluid comes out across the • Localized area of ischemic necrosis either due ependymal lining of ventricles and accumulates in to sudden arterial occlusion or impaired the periventricular white matter. venous return is called infarct and the phenomenon is called infarction. *Cerebral edema is more dangerous, because, the • Types cerebrum may herniate through foramen magnum and patient may die. • Based on presence or absence of infarction – Septic infarct – presence of infection in infarct. – Bland infarct - absence of infection in infarct.

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• Based on color – Pale or anemic infarct • Effects of abnormal blood flow – Red or – Arterial dilatation causes increased blood flow. It is called hyperemia. Most common cause of infarct – Sudden arterial occlusion causes infarction. – Arterial occlusion, caused by thrombus or – Diminised arterial blood flow cases atrophy embolus

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• Characteristics of pale infarct • Characteristics of red infarcts – Caused by arterial occlusion – Caused by impaired venous return – Occurs in solid organs – heart, kidney, liver, spleen – Occurs in loose and previously congested tissue, etc. like – Edema usually absent. • Intestine (in strangulated inguinal hermia, intestinal • Atheroma and obstruction) • Lung – Superimposed thrombus formation on coronary • Testis (in testicular torsion) artery atheroma -> occlusion of artery and • Overy (in twisting of ovary) ischemic necrosis. • Valva etc. – Usually, edema present.

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• Impaired venous return and infarct • Oxygen content of blood – Impaired venous return causes stasis of blood in capillaries -> gradual diminishing of arterial blood flow – Diminished blood oxygen enhences infarction. -> and infarction. Causes are • Factors influencing infarction • Hypoxic condition of individual – Oxygen contents of blood. • Anemia – Rate of development of arterial occlusion • Carbon monoxide poisioning – Nature of vascular supply • Chronic obstructive pulmonary diseases (COPD) – Tissue vulnerability to hypoxia • Heart diseases – Cardiorespiratory status of individual

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• Rate of develpment of arterial occlusion • Tissue vulnerability of hypoxia, examples – Rapid rate of arterial occlusion enhances – Brain is more susceptible to hypoxia and can not infarction. tolerate hypoxia more than 5 minues. • Nature of Vuscular supply – Heart, kidney, liver, adrenal gland can tolerate up – Tissue with dual blood supply is less sensitive to to 30 minutes. infarction, exaples – Skeletal muscle can tolerate for 2 hours. • Lungs [bronchial and pulmonary artery] • Liver [hepatic artery and portal vein] • Hand and forearm [radial and ulner artery]

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• Cardio-respiratory status of individual • If the ischemic zone – like myocardial infarction – – Pre-existing cardiac or pulmonary disease enhences is reperfused infarction. – Reoxygenation following reperfusion causes increased • Shape of infarct generation of oxygen derived free redicals from – Wedge shaped – apex towards occlusion and base parenchimal cells, endothelium and infiltrating towards periphery of organ leucocytes, and cause cell damage. • Reperfusion injury – Blood calcium enters early in cells due to abnormal permeability of reversible injured cells. Calcium – It means reversibly injured cells of ischemic tissue may activates lysosomal enzymes and causes irreversible undergo irreversible injury following reperfusion. cell injury. – In irreversible cell injury calcium derived from – Again blood calcium in dying cells causes mitochondria activates lysosomal emzymes and cause hypercontruction of myofibrils and leads to damage of cells. contraction band necrosis.

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Hyperemia and Congestion

• Hyperemia • Example of hyperemia – Increased volume of blood in an effected tissue or – Hyperemia in fever. Skin become red due to part of tissue due to arteriolar dilatation is called hyperemia. Following hyperemia radiation of hyperemia. temperature from blood to atmospherere and – Mechanism: It is an active process. Arterial or temperature falls in fever. arteriolar dilatation by sympathetic neurogenic – Hyperemia in exercise stimulation or vesoactive amines – like histamine and serotonin –> Increased flow of blood in *Hyperemia is helpful for us. capillaries -> Tissue become red.

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• Congestion • Causes of congestion – Increased volume of blood in an affected tissue or – Congestive cardiac failure (CCF) leads to entire part of tissue due to impaired venous return is body congestion. called congestion. – Impaired venous return in limb leads to localised – Mechanism: It is passive process. Impaired venous congestion return -> stasis of blood in capillaries -> causes • Examples decreased arterial flow -> tissue become blue – Following long journey (cyanosis) due to deoxygenated blood. – Long period of standing

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• Changes in lungs in congestion • Color of skin in – In acute congestion following myocardial infarction fluid leaks in alveolar spaces, termed wet lungs – Hyperemia – Red – In chronic congestion – Congestion - Bluish • Dilatation and rupture of septal capillaries • Minutes intra-alveolar hemorrhage • Breakdown of red cells. • Engulfment of iron of red cells by the alveolar macrophages and formation of hemosiderin laden macrophage, called heart failure cell. Heart failure cell is found in alveolar septum. • When alveolar septum become thick due to fibrosis and hemosiderin pigments, is called brown indurations.

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• Changes in liver in congestion – Nutmeg Liver • Cardiac cirrosis • Distended central vein with blood, congested red zone – Following long standing chronic congestion death of hepatic lobule around central vein, with uncongested of central hepatocytes of hepatic lobule and pink rest zone around around red zone is called Nutmeg fibrosis called cardiac cirrhosis. liver. • Changes in spleen in congestion – Central hemorrhagic necrosis – Enlarge spleen in acute congestion • Following severe cardiac failure necrosis of central hepatocytes of hepatic lobule with hemorrhage around – Fibrosis and hemosiderin causes siderofibrotic central vein, called central hemorrhagic necrosis. nodule following chronic congestion. *Hemosiderin – Iron obtained from red cell breakdown form hemosiderin.

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Hemorrhage • Echymoses: Large and blotchy [eruption like] haemorrhagic spot is called echymoses. Extravasation of blood is called hemorrhage • Hematoma: Accumulation of significant • Types amount of blood in tissue is called hematoma. – Petechae : Minute pin point hemorrhage is called • Hemothorax: Accumulation of blood in pleural petechae or petechial haemorrhage. It occurs in space is called hemothorax. • Skin • Hemoperitoneum: Accumulation of blood in • Mucosa peritoneal space is called hemoperitoneum. • Serous surfaces • Hemopericardium: Accumulation of blood in – Purpura: hemorrhagic spot larger than petechae pericardial space is called hemopericardium. [up to 1 cm] is called purpura. Found in ITP.

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Thrombus and Thrombosis • Types: According to nature – Mural thrombus • Solid or semisolid mass formed by the • Heart chamber constituents of blood is an uninterupted • Great vessels cardiovascular system is called thrombus and – Occlusive thrombus the phenomenon or the process of thrombus – Propagating thrombus formation is called thrombosis. – Saddle thrombus • Types: According to site of formation – Coraline thrombus – Cardiac thrombus: Originates in heart chamber – Consecutive clot thrombus – Venous thrombus: Originates in vein *Fragmentation of tail of propagating thrombus – Arterial thrombus: Originates in artery usually leads to embulus.

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• Thrombus does not occur in blood because – Balance prothrombotic and antithrombotic and antithrombotic role of endothelium. • Difference between blood clot and thrombus – Presence of natural anticoagulant – heparin. – Clot occurs in non-streaming blood. – Continuous blood flow – Example: Blood clot in test tube, glass slide and • Prevent platelet aggregation after death. • Dilute coagulation factors – Clot in in streaming blood is thrombus. • Brings inhibitor of coagulation factor

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• Antithrombotic role of endothelium • Thrombotic role of endothelium – Secrets prostacyclin (PGI ) and nitric oxide that – Produces von Willebrand factor - that makes 2 inhibits platelet aggregation. bridges between endothelium and platelets during thrombosis. – Secretes heparin like molecules. – Synthesizes tissue factor – that activates extrinsic – Secrets tissue plasminogen activator. clotting cascade. – Secretes inhibitor of plasminogen (fibrinolysin) activator and prevents fibrinolysin activation.

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• Virchow’s triad of thrombus • Causes of changes in endothelium / Endothelial – Changes in endothelium [endothelial injury] injury – Changes in normal blood flow – Direct endothelial injury • Traumatic vascular injury – Changes in constituent of blood [hypercoagubility • Inflammatory vascular injury [vasculitis] of blood] – Myocardial infarction – Bacterial toxin – Hemodynamic stress of hypertension – Hypercholesterololemia – Products absorbed from cigarette smoke – nicotine – Snake venom etc.

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• Causes of alteration in normal blood flow [turbulence] – Atherosclerosis • Mechanism of thrombosis following – Myocardial infarction turbulence and stasis of blood – Mitral stenosis – Loss of laminar blood blow – orientation of platelets on endothelial surface. – Aneurysm – Prevention of dilution of coagulation factors – Hyperviscocity of blood – Retardation of inflow of clotting factor inhibitor -> • Polycythemia thrombus formation. • Multiple myeloma

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• Causes of hypercoagubility of blood • Common sites of thrombus formation – Primary hypercoagubility [genetic disorder] – Vein [venous or phlebothrombosis] – Secondary hypercoagubility • Deep calf vein thrombosis • Popliteal vein • Prolonged bed rest or immobilization • Internal iliac vein etc. • Tissue damage following *Tend to grow in the direction of blood flow i.e. towards heart. – Big surgery – Arteries – Burn etc. • Coronary artery • Myocardial infarction • Cerebral artery • Disseminated cancer [cancer cell produces • Femoral artery etc. procoagulant] *Usually superimposed on atherosclerotic plaque or occurs • Smoking [unknown cause] following arteritis and tend to grow in retrograde direction of blood flow • Oral contraceptives

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• Thrombogenesis • Aggregated platelets form platelet plaque. – Endothelial injury and exposure of subendothelial • Activation of intrinsic coagulation pathway on collagen. platelet plaque and formation of fibrin thread. – von Willebrand factor secreted by endothelium • Platelets and fibrin make platelet-fibrin plaque makes bridge between endothelium and collagen. and formation of thrombus. It has two receptor, one for collagen and another for platelets. – After adhession of platelets with collagen dense bodies of plate lets releases • Calcium: needed for coagulation cascade and • ADP: needed for further platelet aggregation.

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• Fate of thrombus – Either attached at the site of origin – Or detached from the site of origin • Fate of detached thrombus • Fate of attached thrombus – Detached from the site of origin and transported – Dissolution by fibrinolysin by blood as an embolus. – Propagation: Small thrombus may propagates -> – It is the most common type of embolus and is become larger -> occludes vessels. called thromboembolus. – Recanalization – Organiztion: Inflammation induced by thrombus causes fibrosis and incorporation of thrombus in vascular wall called organization.

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Embolus and Embolism

• Solid, liquid or gaseous mass transported by • Systemic arterial embolism blood from its point of origin or from its point – Embolus travels within arterial circulation and of entry to a distant place and is impacted. impacts in arteries is systemic embolism. The mass is called embolus and the process of – Effects impaction is called embolism. • Myocardial infarction following coronary artery • Types occlusion by embolus. – Solid – Liquid – Gaseous embolus

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• Paradoxical embolus • Air/Gas Emboli – Embolus originating at venous side, enters arterial – Gas bubbles may cause vascular occlusion and side along pressure gradient is called paradoxical ischemia in gas embolism. embolus and the impaction is called paradoxical – May enter into circulation following embolism. • Chest wall injury in road traffic accident – Causes • During obstretric procedure • Interatrial septal defect – Amount of gas needed for embolism is more than • Interventicular septal defects 100 cc. • Patent ductus arteriosus [that connect aorta with pulmonary trunk in intrauterine life]-associated with pulmonary hypertension.

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• Decompression sickness • Pathogenesis – Sickness following a particular form of gas – Under compression [high pressure] -> liquefaction embolism caused by sudden changes in of nitrogen of breathed air in blood and tissue of atmospheric pressure is called decompression sea diver or other workers. sickness. – Liquefied nitrogen becomes bubble following – Affected individual decompression [release of pressure] -> when diver • Deep sea diver ascends rapidly at sea level. • Underwater construction worker – Bubbles of gaseous nitrogen forms gas embolism. • Mine workers etc.

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• Types of decompression sickness • Chronic decompression sickness or caisson – Acute or bends: Characterized by disease • Severe pain due to ischemia due to gas embolism in – Persistent gas emboli in skeletal system causes skeletal muscles and tissue in and around joint. ischemic necrosis in head of • Severe pain causes arching of affected individual. Due • Humerus arching it is called bend. • Tibia – Treatment • Femur • Individual is placed in compression chamber to make *Chokes: Sometimes, gas emboli may cause respiratory the bubbles of nitrogen liquid. Subsequently, slow distress, called chokes. It results form pulmonary decompression is allowed so that bubbles do not hemorrhage and focal atelactasis of lung following reform to make an embolus. pulmonary gas embolism.

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Shock

• Widespread hypoperfusion of tissue due to • Types of shock disparity between cardiovascular system and – Hypovolumic shock blood volume that may threatened life is – Cardiogenic shock called shock. – Septic shock • End result of shock – Neurogenic shock – Hypotension, followed by impaired tissue – Anaphylactic shock perfusion and cellular hypoxia.

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• Cardiogenic shock: due to cardiac diseases – Myocardial infarction • Hypovolumic shock [Hypovolumia of blood] – Endocarditis – Causes of hypovolumia – Ventricular arythmia etc. • Acute blood loss following road traffic accident, during • Septic shock delivery etc. – Most common causes: Gram-negative organism • Diarrhea • E. coli • Vomiting • Klebsiaella • Extensive burn • Enterobacter • Extensive trauma • Pseudomonus • Bactaroids etc.

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• Less common causes: Gram-positive • Pathogenesis of septic shock: LPS or organisms peptidoglycan causes – Streptococci – Injury to endothelium -> increased vascular – Pneumococci etc. permeability -> Reduction of effective circulatory • Endotoxic shock: Lipopolysaccharide (LPS) is blood volume. – Injury to leucocytes -> Release of toxins -> further an endotoxin derived from gram-negative endothelial injury and reduction of blood volume. organism is associated with shock. Thus septic – Injury to platelets -> release of toxin -> further shock is called endotoxic shock. endothelial injury and reduction of blood volume. • Peptidoglycan present in cell wall of Gram- – Activation of complement system by the alternate positive organism is also associated with pathway -> production of vasoactive C3a and C5a -> vasodilatation and increased vascular permeability -. septic shock. Reduction of effective circulating blood volume.

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• Vasoactive amines, histamine and serotonin released from the injured endothelium, • Consumption coagulopathy leucocytes and platelets and vasoactive complement products, C3a and c5a causes – DIC (disseminated intravasular coagulation) is characterized by numerous thrombi formation – Vasodilatation and increased vascular throghout the vascular system followed by permeability. Peripheral pooling of blood bleeding. As bleeding occurs following following vasodilatation and hypovolumia consumption of platelets and coagulation factors following increased vascular permeability, thus called consumption coagulopathy. decreased effective circulating blood volume -> shock.

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• Neurogenic shock • Anaphylactic shock: IgE mediated – Spinal cord injury hypersensitivity reaction – Anesthetic accident etc. – Systemic vasodilatation and Loss of vascular tone->peripheral polling of blood -> – Increased vascular permeability reduction of effective circulatory blood volume -> disparity between cardiovascular system and Thus reduction of effective circulatory blood volume blood volume -> shock. -> disparity between cardiovascular system and blood volume -> shock.

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• Early compensated stage – Body can compensate and recover from shock • Stages of shock without supplement by infusion or transfusion. – Early compensated stage – Mechanism of compensation and recovery – Progressive decompensated stage • Following blood loss – Irreversible stage – Peripheral vasoconstriction – Decreased cardiac output – Decreased renal blood flow – Renin secretion from juxtaglomerular apparatus and activation of renin angiotensin axis. – Secretion of aldosterone and absorption of sodium and water from renal tubules.

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• Activation of renin-angiotensin-aldosterone • Progressive decompensated stage axis and increased ADH secretion following – Body tries to compensate and recovered from shock but can not recover without supplement by hypovolumia leads to increased blood volume infusion and transfusion. and recovery from shock. – Mechanism • Following blood loss – Peripheral vasoconstriction – Decreased cardiac output – Decreased renal blood flow – Renin secretion from juxtaglomerular apparatus and activation of renin angiotensin axis. – Secretion of aldosterone and absorption of sodium and water from renal tubules.

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• Activation of renin-angiotensin-aldosterone • Irreversible stage axis and increased ADH secretion following – Body tries to compensate. Infusion or transfusion hypovolumia leads to increased blood volume given but no recovery. and recovery from shock. Patient only recovers when supplemented by infusion or transfusion.

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• Morphological changes in tissue in shock – Hypoxia following shock causes injury in all tissue, but main threats to life from in juries are • Brain • Heart • Lungs • Kidney Thanks – Brain: Ischemic liquefaction necrosis – Heart: Ischemic coagulation necrosis – Lungs: Diffuse alveolar damage and adult respiratory distress syndrome (ARDS) – Kidney: Acute tubular necrosis (ATN).

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