Hemodynamic Disorders PDF

Hemodynamic Disorders Assist. Prof. Dr. Ziad Amran Department of Pathology Faculty of Medicine and Medical Sciences Thamar University Dhamar, Yemen  Overview Hyperemia Congestion Edema Ischemia Thrombosis Embolism Infarction Hemorrhage Sho...

Hemodynamic Disorders Assist. Prof. Dr. Ziad Amran Department of Pathology Faculty of Medicine and Medical Sciences Thamar University Dhamar, Yemen  Overview Hyperemia Congestion Edema Ischemia Thrombosis Embolism Infarction Hemorrhage Shock Gangrene Normally..Homeostasis Fluid movement between the vascular and interstitial spaces is governed mainly by two opposing forces: +Vascular hydrostatic pressure: Higher on arteriolar side Lower on venular side Lowest in interstitium the blood pushing against the walls of the capillaries. +Colloid osmotic pressure, produced by plasma proteins (mainly albumin) Only a small net outflow of fluid into the interstitial space, which is drained by lymphatic vessels. Ischemia Hyperemia and Congestion  Hyperemia and Congestion Both refer to an increase in blood volume within a tissue. + Hyperemia is an active process , arteriolar dilation and increased blood inflow. Tissues are redder than normal coz of oxygenated blood. +Congestion is a passive process, impaired outflow of venous blood from a tissue. Tissues have an abnormal blue-red color (cyanosis) due to accumulation of deoxygenated hemoglobin.  Hyperemia and Congestion Active Passive Arterial Venous congestion localized Generalized Physiological Pathological Chronic Acute Chronic Acute Exercising Acute Inflammation Acute heart failure Tumor Uterus Lymph node Chronic heart enlargement failure= Heat therapy Chronic venues congestion CVC Massive myocardial infarction Massive pulmonary embolism Sever toxemia→ stope of heart pregnancy Varicose veins  Congestion ACUTE LOCAL VENOUS CONGESTION Sudden occlusion of a vein (by tourniquet, thrombus,…) Edema, Hemorrhage CHRONIC LOCAL VENOUS CONGESTION Gradual Incomplete Venous occlusion: Pregnancy, Cirrhosis, Mitral Stenosis, Left ventricular failure Edema, Hemorrhage, Stasis (leading to thrombosis), Development of varocsity. Example: Lung: Interstitial edema, ACUTE GENERAL VENOUS CONGESTION Acute Heart failure Rapid generalized congestion of organs and generalized edema CHRONIC GENERAL VENOUS CONGESTION Right ventricular failure. Effect: Edema: ++ Capillary Pressure, ++ Permeability, Organs congestion. Example LIVER, Spleen. * Long standing congestion Stasis of poorly oxygenated blood chronic hypoxia death of cells Fibrosis Increased capillary pressure rupture Foci of hemorrhage Acute pulmonary congestion (Lung) Blood-engorged alveolar capillaries Variable degrees of alveolar septal edema Intraalveolar hemorrhage (Presence of intact RBCs in alveolar cells with fresh hemorrhage) Acute Pulmonary Congestion occur in acute left ventricular failure Chronic pulmonary congestion Septa become thickened and fibrotic. The alveolar spaces contain numerous macrophages laden with hemosiderin “heart failure cells” derived from phagocytosed red cells. Chronic Pulmonary Congestion is due to Chronic congestive heart failure “CHF” Acute hepatic congestion. The central vein and sinusoids are distended with blood. Centrally located hepatocytes⇨ may be necrosis Periportal hepatocytes ⇨ less severe hypoxia and may develop only reversible fatty change. Chronic passive congestion of the liver “Nutmeg” appearance Grossly: Enlarged, Darked brawn, Firm, Heavy Show dark red (congestion) and yellowish (fatty liver). Nutmeg Shrunken and congested centrilobular areas impart the characteristic “nutmeg” appearance to the liver. This finding is most commonly associated with right-sided congestive heart failure.  Chronic venous congestion, liver Central vein Central vein Low power Central sinusoidal congestion and necrosis Microscopically: Pale areas are coagulative necrosis, dark areas are normal viable tissue (many RBCs, and hepatocytes are atrophied). + 60% of lean body weight is water. + Two thirds is intracellular. + ECF: most of the extracellular fluid is in the that lies between cells + Only 5% of the body’s water is in blood plasma. Edema Definition Accumulation of abnormal amounts of fluid in the intercellular tissue spaces and/or body cavities (Serous sacs). Such accumulations are often referred to as effusions. + Extravasate : to move out of the vasculature (Extravasation). Effusions into body cavities: Hydrothorax: within thorax, around lungs; also pleural effusion. Hydropericardium: Fluid in the pericardial sac. Hydroperitoneum or ascites: Fluid in the peritoneal cavity.  25 mmHg 12 mmHg 32 mmHg Transudate: (Fluid leakage). Edema: Excessive fluid in An extra-vascular fluid with low the interstitial tissue or body protein content & low specific cavities which is either exudate or gravity. transudate. Exudate : An inflammatory extravasation of fluid that has a high protein concentration & cellular debris with high specific gravity.  Lymphatic obstruction Tissue capillary Lymph vessel ↓HP ↑HP Heart failure ↑ protein /inflammation ↓OP Ascites (liver cirrhosis) ↑ salts in tissue – Sodium ↑OP and Water Retention (e.g., vein renal failure) Hypoproteinemia Loss of protein/ Renal syndrome/ proteinuria ↓protein synthesis- liver disease Permeability ↓protein intake Histamine –allergy Vein Congestion Inflammation Hypoxia  Lymphangitis, Lymphadenitis Sodium and Water Retention Excessive retention of salt (and its obligate associated water) can lead to edema by increasing hydrostatic pressure  Pathophysiology of hypoproteinemia Decreased serum protein reduces the oncotic pressure of the blood, leading to loss of fluid from the intravascular compartment, or the blood vessels, to the interstitial tissues, resulting in edema.  Pitting Oedema: generalized or localized (transudate) Types of oedema Non-pitting (hard) Oedema: It occurs in cases of lymphatic oedema & sometimes in inflammatory oedema. Local General Local increases in intravascular pressure Generalized increases in venous pressure ↑HP ↓OP Inflammation Obstruction Allergy Increased Venous angioneurotic permeability Hyporproteinemia Chronic right sided obstruction heart failure Lymphatic obstruction acute or chronic elephantiasis-= Start in lower limbs filariasis then generalized Proteinuria/nephritic or nephrotic ↓protein syndrome synthesis- liver disease ↓protein intake/ Malnutrition, Malabsorption  Lymphatic Obstruction Related Edema Massive edema of the right lower extremity (elephantiasis) in a patient with obstruction of lymphatic drainage Elephantiasis due to filariasis by Wuchereria bancrofti  Trauma, Fibrosis, invasive tumors, and infectious agents can cause obstruction or disruption of the lymphatic vessels and impair clearance of interstitial fluid resulting to lymphedema. Pathways leading to systemic edema resulting from heart failure, renal failure, or reduced plasma osmotic pressure, which has several causes including liver failure. Pathologic Consequences of Chronic Congestive Heart Failure  Anasarca – severe, generalized edema – ana= throughout, sark= flesh – Most commonly used to describe fetal or neonatal whole-body, subcutaneous swelling. and accumulation of fluid in body cavities.  Clinical features of edema Subcutaneous Edema  + Subcutaneous edema can be diffuse or localized.  More in parts of the body positioned the greatest distance below the heart, where hydrostatic pressures are highest.  Distribution is influenced by gravity termed dependent edema.  Usually appears in the legs when standing, and sacrum when recumbent.  It signals potential underlying cardiac or renal disease.  Can impair wound healing and clearance of infections. Pitting Oedema: generalized or localized (transudate) Non-pitting (hard) Oedema: It occurs in cases of lymphatic oedema & sometimes in inflammatory oedema.  Clinical features of edema + Edema from renal dysfunction or nephrotic syndrome often manifests first in loose connective tissues (e.g., the eyelids (periorbital edema)  Clinical features of edema Pulmonary Edema  A common clinical problem seen in Left Ventricular Failure.  Can also occur with renal failure, acute respiratory distress syndrome, and pulmonary infection.  Fluid accumulates in the alveolar septa and impedes oxygen diffusion, the lungs are often 2-3 times normal weight.  Secretions yield frothy, blood-tinged fluid – a mixture of air, edema, and extravasated red cells. Pulmonary edema  BRAIN EDEMA Brain edema can be localized (abscess or tumor) or generalized, depending on the pathologic process or injury. A generalized accumulation of fluid in brain Possible causes: A. Infection like encephalitis B. Trauma C. Obstruction to normal venous blood outflow D. Neoplasms Morphology: Grossly swollen brain with narrowed sulci and distended gyri. The brain takes on a flattened appearance as it presses against the solid skull. , the brain stem vascular supply can be compressed, leading to death due to injury to the medullary centers controlling respiration and other vital functions.. The brain can herniate  Clinical features of edema Peritoneal Effusion  Ascites  Results more commonly from portal hypertension.  Prone to seeding by bacteria leading to infections.  It is reduction of arterial blood supply to a tissue. Ischemia Chronic Thrombosis Acute Gradual Sudden Complete Incomplete Inflammation- Embolism syphilis Surgical ligature of Degeneration - an artery Atherosclerosis Compression - Strangulation of tumors. vessels spasm -Raynaud’s disease Coronary spasm in Ischemia effects young Gradual Incomplete Sudden Complete With collateral no effect With collateral no effect Without collateral Without collateral -Degeneration infarction or gangrene -Atrophy -fibrosis  Embolism Impaction of undissolved substance in a vessel. Embolism →emboli → Transferred mass is called embolus. Can arrest anywhere in the vascular tree. Causing partial or complete occlusion. It often causes tissue dysfunction or infarction. Sites: may be pulmonary , portal, systemic or paradoxical:  Embolism Nature of Emboli: Solid/semisolid, Gaseous, Liquid. Types of embolism Majority of the emboli are dislodged thrombi, hence the o Thrombo-embolism (Septic or Aseptic) term thromboembolism. o Fat (Bone marrow , Fatty liver, burns, drugs) o Bone o Malignant emboli o Bacteria o Foreign body (Cotton, plastic) o Amniotic fluid o Air o Parasitic – ova  Embolism effects With collateral no effect With bacteria- Small -resolution septic- pyaemia Without collateral Large No bacteria infarction  Pulmonary Thromboembolism  Most common form of Thromboembolic disease. The incidence of (PE) is 2 to 4 per 1000 hospitalized patients.  About 100,000 deaths per year in the United States In more than 95% of cases, venous emboli originate from thrombi within deep leg veins proximal to the popliteal fossa. Emboli from the legs are carried to the vena cava to the right atrium to the pulmonary circulation.  Depending on the size of the embolus, it can: Occlude the main pulmonary artery. Straddle the pulmonary artery bifurcation (saddle emboli). Pass into the smaller, branching arterioles. Embolus can pass through an atrial or ventricular defect and enters the systemic circulation (paradoxical embolism, rare ).  Major clinical and pathologic features of PE (1) Most PEs (60%–80%) are small and clinically silent. (undergo organization and become incorporated into the vascular wall, some cases, leaves behind bridging fibrous webs). (2) A large embolus that blocks a major pulmonary artery can cause sudden death. (3) Embolic obstruction of medium-sized arteries ⇉rupture of capillaries ⇉ cause pulmonary hemorrhage. * In normal person doesn’t cause pulmonary infarction (dual circulation; bronchial circulation and pulmonary arteries). * In the setting of left-sided cardiac failure (diminished bronchial artery perfusion) can lead to a pulmonary infarct. (4) Embolism to small end-arteriolar pulmonary branches usually causes infarction. (5) Multiple emboli occurring through time can cause pulmonary hypertension and right ventricular failure (cor pulmonale). (occur when emboli obstructs 60% of the pulmonary circulation). (6) Patient who had one PE is at high risk for more.  Systemic Thromboembolism Most systemic emboli (80%) arise from intracardiac mural thrombi. Two-thirds of these are associated with left ventricular infarcts. 25% with dilated left atria (e.g., secondary to mitral valve disease). The remainder originate from (1) aortic aneurysms, (2)thrombi overlying ulcerated atherosclerotic plaques, (3) fragmented valvular vegetations, (4)the venous system (paradoxical emboli); (5)10% to 15% of systemic emboli are of unknown origin...Systemic Thromboembolism Arterial emboli can travel to anywhere; final resting place depends on their point of origin and the relative flow rates of blood to the downstream tissues. Common arteriolar embolization sites: (1) the lower extremities (75%). (2) central nervous system (10%) (3) intestines, kidneys, and spleen are less common targets. The consequences of embolization depend on the caliber of the occluded vessel, the collateral supply, and the affected tissue’s vulnerability to anoxia. Arterial emboli often lodge in the end arteries and cause infarction.  Fat Embolism-fetal Can be found in pulmonary vasculature after fractures of long bones, soft-tissue trauma and burns, vigorous cardiopulmonary resuscitation (CPR) and Drugs. Occurs in 90% of individuals with severe skeletal injuries.  Fat Embolism syndrome  Minority of patients, but fatal in 10%.  Manifestations: Pulmonary Insufficiency. Neurologic Symptoms. Anemia – red cell aggregation and hemolysis. Thrombocytopenia – associated to platelet adhesion to fat.  Clinical signs and symptoms appear 1 to 3 days after injury.  Sudden onset of tachypnea, dyspnea, tachycardia, irritability, and restlessness.  Can progress rapidly to delirium or coma.  A diffuse petechial rash (20%–50% of cases) due to rapid onset of thrombocytopenia and (useful diagnostic feature).  Pathogenesis of fat embolism syndrome (1)Mechanical obstruction: Fat microemboli occlude pulmonary and cerebral microvasculature, both directly and by triggering platelet aggregation. (2) Biochemical injury: + fatty acid release from lipid globules, which causes local toxic endothelial injury. + free radical and protease release (from platelet activation and granulocyte recruitment) cause vascular assault too.  Amniotic Fluid Embolism  It is Complication of labor and the immediate postpartum period.  SOURCE: entry of amniotic fluid (and its contents) into the maternal circulation via tears in the placental membranes and/or uterine vein rupture.  The mortality rate approaches 80%, making it the most common cause of maternal death in the developed world. (10% of maternal deaths).  85% of survivors suffer some form of permanent neurologic deficit.  Presentation: Sudden Severe Dyspnea Cyanosis Hypotensive Shock Neurologic Impairment Seizures and Coma ⇓ Disseminated intravascular coagulation (DIC)  Morbidity and mortality: From biochemical activation of the coagulation system and the innate immune system by substances in the amniotic fluid, not from mechanical obstruction of pulmonary vessels.  Pathophysiology of Disseminated Intravascular Coagulation (DIC) Coagulation factor III thromboplastin tissue factor  Systemic activation of blood coagulation.  Results in generation and deposition of fibrin.  Leading to microvascular thrombi contributing to multi-organ dysfunction.  Consumption of clotting factors and platelets can result in life-threatening hemorrhage. activated partial thromboplastin time (aPTT) Prothrombin Time (PT)  Air Embolism Gas bubbles within the circulation can form frothy masses that obstruct vascular flow and cause distal ischemic injury.  A large volume of air around 100cc is needed to produce clinical manifestations.  Common among deep sea divers and astronauts.  When air is breath at high pressure, increased amount of gas (nitrogen) are dissolved in blood & tissues. If the diver ascends too rapidly, the nitrogen comes out of solution into the tissues and blood.  Bends – rapid formation of gas bubbles within the skeletal system, characteristically arched backs.  Chokes - gas bubbles can cause edema, hemorrhage, and focal atelectasis or emphysema leading to this form of respiratory distress.  Caisson Disease – Chronic form of Decompression Sickness, leads to multiple foci of ischemic necrosis commonly in the tibia, femoral heads, and humerus.  INFARCTION  Area of ischemic necrosis caused by (sudden cut of blood supply ) occlusion of either the arterial supply or venous drainage.  Affecting the heart and the brain is a common. 40% of all deaths in the United States are a consequence of cardiovascular disease. (mostly myocardial or cerebral infarction).  Pulmonary infarction is a common clinical complication.  Bowel infarction often is fatal.  Ischemic necrosis of distal extremities (gangrene) causes substantial morbidity in the diabetic population.  Causes of Infarction Arterial occlusion: + underlies the vast majority of infarctions (thrombosis and embolism). arterial occlusions 99%. + Less common causes of arterial obstruction: (1)vasospasm, (2)expansion of an atheroma due to intra-plaque hemorrhage, and (3) extrinsic compression of a vessel (like tumor, or hernial sac) (4) vessel twisting (e.g., in testicular torsion or bowel volvulus), (5) traumatic vascular rupture. Venous thrombosis: + the more common outcome is simply congestion. + Infarcts caused by venous thrombosis usually occur only in organs with a single efferent vein (testis or ovary).  Factors that Affect Infarction 1.) Nature or Anatomy of Vascular Supply:  The availability of an alternative blood supply lessens the chances of infarction.  Examples of areas with dual blood supply: Lungs (Bronchial and Pulmonary) Liver (Hepatic and Portal) Hand and Forearm (Radial and Ulnar)  Organs with end-arterial supply (prone to infarction) Spleen Kidney  Factors that Affect Infarction 2.) Rate of Occlusion  Slow developing occlusions are less likely to result to infarct, it provides time for development of collateral pathways for perfusion (e.g. Small interarteriolar anastomoses in the coronary arteries of the heart).  Factors that Affect Infarction 3.) Tissue sensitivity to Hypoxia  Neurons undergo irreversible damage when poor of blood supply for only 3-4 minutes.  Myocardial cells can die 20-30 minutes due to ischemia.  Fibroblasts in the myocardium can last hours. 4.) Hypoxemia  Abnormally low O2 content increases the probability and extent of infarction.  TYPES OF INFARCTION Red infarcts (1) Venous occlusions (ovarian torsion). (2) In loose tissues (e.g., lung) where blood can collect in infarcted zones. (3) Tissue with dual circulations (lung and small intestine); partial-inadequate perfusion by collateral arterial supplies. (4) previously congested tissues (as a consequence of sluggish venous outflow). (5) when flow is reestablished after infarction has occurred (e.g., after angioplasty of an arterial obstruction). pulmonary infarct 53  White infarction  In arterial occlusions in solid organs with end-arterial circulations (heart, spleen, and kidney), tissue density limits the seepage of blood vascular beds.  wedge-shaped, with the occluded vessel at the apex and the organ periphery forming the base.  If the base is a serosal surface, there is an overlying fibrinous exudate.  Lateral margins may be irregular, reflecting flow from adjacent vessels. In acute infarcts, margins are indistinct and slightly hemorrhagic. With time, the edges become better defined(progressively paler infarct) with a narrow rim of hyperemia - inflammation.  3.) Ischemic coagulative infarctions  It takes 4-12 hours for the dead tissue to show microscopic evidence of frank necrosis.  In stable tissue, parenchymal regeneration may occur and stromal architecture is preserved, but most infarcts are ultimately replaced by scar formations.  Brain is an exception to coagulative infarctions because brain infarcts result to liquefactive necrosis. 4.) Septic infarction  When infected cardiac vegetations embolize or when microbes seed necrotic tissues.  The infarct is converted to an abscess with greater inflammatory response.  Hemorrhage It is extravasation of blood from vessels, most often the result of damage to blood vessels or defective clot formation.. Local General Traumatic injury of vessels: accidents, surgery. Hypertension Erosion of vessels e.g. in case of malignant tumors, General venous congestion. tuberculosis & peptic ulcers. Blood diseases as hemophilia, purpura, leukemia Vitamin C or K deficiency Rupture of aneurysm Fever Local venous congestion. Inflammations e.g. bilharzial cystitis. Effects of Hemorrhage Local Effects: Systemic Effects: Hemostasis a-Chronic (repeated) blood loss: b-Rapid blood loss: Very small amount: No effect. - Moderate amounts less than 750-1000 ml of blood: Compensation. Massive amounts more than 1 liter lead to shock.  Types of hemorrhage External Internal , cavity Interstitial tissue a)From skin. b)From respiratory tract: c) From alimentary tract: Hemothorax Hematemesis: Hemopericardium Hemoperitonoum Melena Hemarthrosis hemorrhagic inside joint cavity Bleeding per rectum: d) From urinary tract: hematuria ë) From female genitalia According to type of bleeding vessels: It may appear red (arterial) or blue venous blood). According to size may be: a) Petechial (small spots of hemorrhage) b) Ecchymosis (a bigger patch or patches of hemorrhage), Purpura c) Hematoma (large blood swelling)  Clinical features of hemorrhages.. Into Body cavities Hematoma Extensive hemorrhages can occasionally result in jaundice Large bleeds into body cavities are Accumulation of blood within a from the massive breakdown of described according to location: tissue. red cells and hemoglobin. hemothorax, hemopericardium, ranges in significance from hemoperitoneum, or hemarthrosis (in trivial to fatal. joints).  Title Ecchymosis Purpura Petechiae + Large 1-2 cm subcutaneous + They are minute1-2 mm + Purpura is 3-5 mm hematomas (bruises), red cells hemorrhages into skin, mucous phagocytosed and degraded by hemorrhages. macrophages. membranes, or serosal surfaces. + can result from the same + color changes of a bruise result disorders that cause petechiae, as + Causes: low platelet counts from enzymatic conversion of well as trauma, vascular (thrombocytopenia), defective hemoglobin (red-blue color) to inflammation (vasculitis), and platelet function, and loss of bilirubin (blue-green color) and increased vascular fragility. vascular wall support, as in vitamin eventually hemosiderin (golden- C deficiency brown). A. Punctate petechial hemorrhages of the colonic mucosa, a consequence of thrombocytopenia. B. Fatal intracerebral hemorrhage.  Shock It is Sudden widespread hypoperfusion of cells and tissues.  A state in which diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia. At the start, cellular injury is reversible, but prolonged shock eventually leads to irreversible tissue injury and is often fatal  Types , causes of shock Hypovolemic Shock: Failure of Myocardial pump⇩Cardiac Output Severe hemorrhage and fall of BP. fluid loss Cardiogenic shock: Dehydration Vasodilatation Diarrhea, Vomiting, Myocardial infarction due to coronary occlusion loss of vascular tone Rupture of a valve. Sever burns Rupture of heart. Trauma Severe arrhythmias. fall of BP and Low cardiac output  Extrinsic Compression (Cardiac Tamponade)  Outflow Obstruction (Pulmonary Embolism) Septic shock (Endotoxin shock) Neurogenic shock Anaphylactic shock  Loss of vascular tone “Peripheral vasodilation ⇓Blood Volume ⇓ CO” Neurogenic Shock  Anesthetic accidents  Spinal cord injuries - Neurogenic vasodilation and fall of BP. Anaphylactic Shock - Systemic IgE mediated- vasodilation and Vascular permeability - - hypersensitivity reaction  Septic Shock - Triggered by variety of insults:  Infection (particularly microbial) - Most common is Gram Positive Septicemia - Gram Negative - Fungi  Burns  Trauma  Pancreatitis - Massive outpouring of inflammatory mediators  Arterial Vasodilation  Vascular Leakage  Venous Blood Pooling - End result is organ hypo perfusion, to tissue hypoxia, to cell damage, leading to organ dysfunction and failure to death.  Septic shock Septic shock is triggered by microbial infections and is associated with severe systemic inflammatory response syndrome (SIRS), (burns, trauma, and/or pancreatitis). 50% require treatment in intensive care units(ICU). Septic shock incidence is increasing with time due to (1) immunocompromised hosts (chemotherapy, immunosuppression, advanced age, or human immunodeficiency virus infection). (2) Increasing prevalence of multi-drug resistant organisms in the hospital setting. Inflammatory responses Recognition Microbial cell wall constituents engage receptors on cells of the innate immune system: (1) Toll-like receptors (TLRs) recognize substances containing “pathogen-associated molecular patterns” (PAMPs). (2) G-protein–coupled receptors: detect bacterial peptides. (3) C-type lectin receptors (Dectins). Inflammatory responses Activated immune cells produce numerous cytokines (TNF, IL-1, IFN-γ, IL-12, and IL- 18,), inflammatory mediators (high-mobility group box 1 protein (HMGB1)).] Reactive oxygen species and lipid mediators such as prostaglandins and platelet- activating factor (PAF) are also elaborated. The complement cascade is also activated by microbial components; anaphylatoxins (C3a, C5a), chemotactic fragments (C5a), and opsonins (C3b).  Hyperinflammatory state Counter-inflammatory responses. ⇓⇑ Triggers counterregulatory immunosuppressive mechanisms.(both innate and adaptive immune cells) ⇓ Patients susceptible to superinfections. (1) a shift from proinflammatory (TH1) to anti-inflammatory (TH2) cytokines. (2) anti-inflammatory mediators (soluble TNF receptor, IL-1 receptor antagonist, and IL-10) (3) lymphocyte apoptosis. (4) Induction of cellular anergy (Lack of reaction). Endothelial activation and injury ◇ Inflammatory cytokines loosen endothelial cells tight junctions  vessels leak  accumulation of protein-rich fluid throughout the body. ◇ This impedes tissue perfusion  block nutrient delivery and waste removal. ◇ Activated endothelium upregulates production of nitric oxide (NO) vasoactive mediators (C3a, C5a, and PAF), contribute to vascular smooth muscle relaxation systemic hypotension. Induction of a procoagulant state. “DIC” Inflam.cytokines: ⇑ tissue factor production, ⇑ plasminogen activator inhibitor-1 (⇓ Fibrinolysis). ⇓ tissue factor pathway inhibitor, thrombomodulin, protein C. Vascular leakage, oedema ⇓ blood flow in small vessels… ⇓ washout of activated coagulation factors. SYSTEMIC activation of coagulation…widespread thrombi formation…Consumption of platelets…Thrombocytopenia…Bleeding. Endothelial protein C receptor (EPCR) Metabolic abnormalities Hyperglycemia TNF, IL-1⇒⇑ Catecholamines, Stress hormones ((glucagon, growth hormone, and glucocorticoids) ⇒⇑GLUCONEOGENEIS + Inflam.cytokines ⇒⇓Insulin Release and ⇑ Insulin. Resistance (⇓ GLUT 4 surface receptors for glucose). Glucose Transporter Type 4 Leads to: ⇓ Neutrophil functions…. And Increased adhesion molecule expression on endothelial cells. ◇ In sepsis, initially, ⇑ glucocorticoid production happened, but it maybe followed by adrenal insufficiency: (1) A functional deficit of glucocorticoids (depression of the synthetic capacity). (2) Adrenal necrosis from DIC (Waterhouse-Friderichsen syndrome) ◇ Cellular hypoxia  diminished oxidative phosphorylation  increased lactate production and lactic acidosis (anaerobic glycolysis).  Organ dysfunction ◇ Systemic hypotension, interstitial edema, and small vessel thrombosis all decrease the delivery of oxygen and nutrients  cellular hypoxia. ◇ Mitochondrial damage from oxidative stress impairs oxygen use. ◇ Cytokines and secondary mediators diminish myocardial contractility and cardiac output. ◇ Vascular permeability and endothelial injury can lead to the acute respiratory distress syndrome. ◇ All these factors cause multiple organs failure (kidneys, liver, lungs, and heart)  Death. Severity and outcome of septic shock depends on: ◇ The extent and virulence of the infection, ◇ The immune status of the host, ◇ The presence of other comorbid conditions, ◇ Type and level of mediator production. The multiple factors. ⇓ ◇ Difficult of therapeutic. ⇓ ◇ May had harmful effects in some cases.  Stages of shock: 1) No progressive phase: (compensated) 2) Progressive phase: 3) Irreversible phase: An initial A progressive stage. An irreversible nonprogressive Tissue stage. Cellular and stage. Reflex hypoperfusion & tissue injury is so compensatory onset of worsening severe that even if mechanisms are circulatory & the hemodynamic activated and vital metabolic defects are organ perfusion is derangement, corrected, survival is maintained. including acidosis. not possible. Hypoxia →anaerobic glycolysis Degeneration and necrosis → pooling of blood in the → failure then death microcirculation. Clinical picture: Hypotension. Weak rapid pulse. Shallow rapid respiration Oliguria or anuria. Patient is restless Skin is pale ,cool & sweaty Skin may be warm and flushed (septic shock) 77  Septic shock can initially cause cutaneous Cutaneous vasoconstriction causes vasodilation, so the patient the characteristic “shocky” skin cool and pallor. may present with warm, flushed skin.  Gangrene Clinical term used when a large area of tissue undergoes necrosis. It is massive necrosis (infarction or infections) followed by putrefaction. Putrefaction is caused by Saprophytes bacteria (decompose dead tissue producing hydrogen sulfide and iron, leading to formation of iron sulphide, giving Black color to gangrenous area) Clostridium perfringens Necrosis → putrefaction Types of gangrene Dry Senile Vascular cases +putrefaction Moist Diabetic Bacteria Infection – gangrene Intestinal Infective Gas Artery Artery + vein Gas gangrene Dry gangrene Lung gangrene Moist gangrene Limb crushing Senile gangrene Initiation of Internal organ (strangulated hernia) vascular stasis Diabetic gangrene Progress of diabetes Malnutrition,↓immunity Bed sores atherosclerosis  Types of gangrene Dry gangrene Wet gangrene Gas gangrene  The skin surrounding the affected  An area that is cold, wet from tissue  If the area of necrosis becomes shrinks, wrinkles and turns black. exudates and swollen. infected with bacteria that produce gases as a byproduct.  Dry Gangrene Moist Gangrene Arterial occlusion Venous and arterial occlusion Doe not occur in internal organs Occurs in internal organs Occur in limbs in cases of: Senile, Burger’s,… Occur in limbs in cases of: crush injuries, tight tourniquet, diabetic Slow putrefaction RAPID putrefaction Mild toxemia SEVERE toxemia Affected part is Dry and mummified Edematous and swollen Prominent line of demarcation Poor line of demarcation Line of separation No Line of separation