General Pathology: Derangement of Homeostasis and Hemodynamics I PDF

General Pathology Derangement of homeostasis and hemodynamics I Dr. Hersh A. Ham-Karim PhD Pathology  Homeostasis The term internal environment or milieu interieur for the state in the body in which the interstitial fluid that bath...

General Pathology Derangement of homeostasis and hemodynamics I Dr. Hersh A. Ham-Karim PhD Pathology  Homeostasis The term internal environment or milieu interieur for the state in the body in which the interstitial fluid that bathes the cells and the plasma, together maintain the normal morphology and function of the cells and tissues of the body. The mechanism by which the constancy of the internal environment is maintained and ensured is called the homeostasis. For this purpose, living membranes with varying permeabilities such as vascular endothelium and the cell wall play important role in exchange of fluids, electrolytes, nutrients and metabolites across the compartments of body fluids. The normal composition of internal environment consists of the following components: 2 I. Water. Water is the principal and essential constituent of the body. The total body water in a normal adult male comprises 50-70% (average 60%) of the body weight and about 10% less in a normal adult female (average 50%). The total body water is distributed into 2 main compartments of body fluids separated from each other by membranes freely permeable to water. a. Intracellular fluid compartment. This comprises about 33% of the body weight, the bulk of which is contained in the muscles. b. Extracellular fluid compartment. This constitutes the remaining 27% of body weight containing water. II. Electrolytes. The concentration of cations (positively charged) and anions (negatively charged) is different in intracellular and extracellular fluids: a. In the intracellular fluid, the main cations are potassium and magnesium and the main anions are phosphates and proteins. It has low concentration of sodium and chloride. b. In the extracellular fluid, the predominant cation is sodium and the principal anions are chloride and bicarbonate. Besides these, a small proportion of non-diffusible proteins and some diffusible nutrients and metabolites such as glucose and urea are present in the ECF.  Disturbances of body fluids Oedema The Greek word oidema means swelling. Oedema may be defined as abnormal and excessive accumulation of “free fluid” in the interstitial tissue spaces and serous cavities. The presence of abnormal collection of fluid within the cell is sometimes called intracellular oedema but should more appropriately be called hydropic degeneration Free fluid in body cavities: Depending upon the body cavity in which the fluid accumulates, it is correspondingly known as ascites (if in the peritoneal cavity), hydrothorax or pleural effusion (if in the pleural cavity), and hydropericardium or pericardial effusion (if in the pericardial cavity). Free fluid in interstitial space: The oedema fluid lies free in the interstitial space between the cells and can be displaced from one place to another. In the case of oedema in the subcutaneous tissues, momentary pressure of finger produces a depression known as pitting oedema. The other variety is non-pitting or solid oedema in which no pitting is produced on pressure e.g. in myxoedema, lipedema. The oedema may be of 2 main types: 1. Localised when limited to an organ or limb e.g. lymphatic oedema, inflammatory oedema, allergic oedema. 2. Generalised (anasarca or dropsy) when it is systemic in distribution, particularly noticeable in the subcutaneous tissues e.g. renal oedema, cardiac oedema, nutritional oedema. Depending upon fluid composition, oedema fluid may be: transudate which is more often the case, such as in oedema of cardiac and renal disease; or exudate such as in inflammatory oedema. Feature Transudate Exudate Definition Filtrate of blood plasma without Oedema of inflamed tissue changes in endothelial permeability associated with increased vascular permeability Character Non-inflammatory oedema Inflammatory oedema Protien content Low (less than 1 gm/dl); mainly High ( 2.5-3.5 gm/dl), readily albumin, low fibrinogen; hence no coagulates due to high content tendency to coagulate of fibrinogen and other coagulation factors Glucose Same as in plasma Low (less than 60 mg/dl) content LDH < 0.6 > 0.6 Cells Few cells and cellular debri Many cells, inflammatory as well as parenchymal Pathogenesis of oedema Oedema is caused by mechanisms that interfere with normal fluid balance of plasma, interstitial fluid and lymph flow. The following mechanisms may be operating singly or in combination to produce oedema: 1. Decreased plasma oncotic pressure 2. Increased capillary hydrostatic pressure 3. Lymphatic obstruction 4. Tissue factors (increased oncotic pressure of interstitial fluid, and decreased tissue tension) 5. Increased capillary permeability 6. Sodium and water retention. Diagrammatic representation of pathogenesis of oedema (OP = oncotic pressure; HP = hydrostatic pressure). 1. Renal Oedema Oedema in nephrotic syndrome. Since there is persistent and heavy proteinuria (albuminuria) in nephrotic syndrome, there is hypoalbuminemia causing decreased plasma oncotic pressure resulting in severe generalized oedema (nephrotic oedema). The hypoalbuminemia causes fall in the plasma volume activating renin-angiotensin- aldosterone mechanism which results in retention of sodium and water, thus setting in a vicious cycle which persists till the albuminuria continues. Similar type of mechanism operates in the pathogenesis of oedema in protein-losing enteropathy, further confirming the role of protein loss in the causation of oedema. 2. Cardiac Oedema Generalized oedema develops in right-sided and congestive cardiac failure. Pathogenesis of cardiac oedema is explained on the basis of the following hypotheses. a. Reduced cardiac output causes hypovolemia which stimulates intrinsic-renal and extra- renal hormonal (renin angiotensin-aldosterone) mechanisms as well as ADH secretion resulting in sodium and water retention and consequent oedema. b. Due to heart failure, there is elevated central venous pressure which is transmitted backward to the venous end of the capillaries, raising the capillary hydrostatic pressure and consequent transudation; this is known as back pressure hypothesis. c. Chronic hypoxia may injure the capillary wall causing increased capillary permeability and result in oedema; this is called forward pressure hypothesis. However, this theory lacks support since the oedema by this mechanism is exudate whereas the cardiac oedema is typically transudate. In left heart failure, the changes are, however, different. There is venous congestion, particularly in the lungs, so that pulmonary oedema develops rather than generalized oedema. Cardiac oedema is influenced by gravity and is thus characteristically dependent oedema i.e. in an ambulatory patient it is on the lower extremities, while in a bed-ridden patient oedema appears on the sacral and genital areas. The accumulation of fluid may also occur in serous cavities. 3. Cerebral Oedema Cerebral oedema or swelling of brain is the most threatening example of oedema. The mechanism of fluid exchange in the brain differs from elsewhere in the body since there are no draining lymphatics in the brain but instead, the function of fluid-electrolyte exchange is performed by the blood-brain barrier located at the endothelial cells of the capillaries. 4. Pulmonary Oedema Acute pulmonary oedema is the most important form of local oedema as it causes serious functional impairment but has special features. It differs from oedema elsewhere in that the fluid accumulation is not only in the tissue space but also in the pulmonary alveoli. Etio-pathogenesis. The hydrostatic pressure in the pulmonary capillaries is much lower (average 10 mmHg). Normally the plasma oncotic pressure is adequate to prevent the escape of fluid into the interstitial space and hence lungs are normally free of oedema. Pulmonary oedema can result from either the elevation of pulmonary hydrostatic pressure or the increased capillary permeability  Dehydration Dehydration is a state of pure deprivation of water leading to sodium retention and hence a state of hypernatraemia. In other words, there is only loss of water but no loss of sodium. Clinically, the patients present with intense thirst, mental confusion, fever, and oliguria. Etiology. Pure water deficiency is less common than salt depletion but can occur in the following conditions: 1. GI excretion: e.g, Severe vomitings and Diarrhoea 2. Renal excretion: e.g., Acute renal failure in diuretic phase and Extensive use of diuretics 3. Loss of blood and plasma: e.g., Severe injuries, severe burns 4. Loss through skin: e.g., Excessive perspiration and Hyperthermia 5. Accumulation in third space: e.g., Sudden development of ascites and Acute intestinal obstruction with accumulation of fluid in the bowel.  Disturbances of electrolytes In health, for electrolyte homeostasis, the concentration of electrolytes in both intracellular and extracellular compartments should be within normal limits. Normal serum levels of electrolytes are maintained in the body by a careful balance of 4 processes: their intake, absorption, distribution and excretion. Disturbance in any of these processes in diverse pathophysiologic states may cause electrolyte imbalance. Among the important components in electrolyte imbalance, abnormalities in serum levels of sodium (hypo- and hypernatraemia), potassium (hypo- and hyperkalaemia), calcium (hypo- and hypercalcaemia) and magnesium (hypo- and hypermagnesaemia) are clinically more important..  Hyponatraemia  Hypernatraemia a. Gain of relatively more water than a. Gain of relatively more salt than loss loss of sodium of water Excessive use of diuretics IV infusion of hypertonic solution Hypotonic irrigating fluid Excessive sweating (in deserts, administration heat stroke) b. Loss of relatively more salt than water b. Loss of relatively more water than salt Excessive use of diuretics Diabetes insipidus Renal failure (ARF, CRF) Induced water deprivation (non- availability of water, total fasting)  Hypokalaemia  Hyperkalaemia a. Excessive potassium intake a. Decreased potassium intake Excessive or rapid infusion Anorexia containing potassium IV infusions without potassium Large volume of transfusion of Diet low in potassium stored blood b. Excessive potassium excretion b. Decreased potassium excretion Loss from GI tract (e.g. vomitings, Oliguric phase of acute renal failure diarrhoea, laxatives) Adrenal cortical insufficiency (e.g. Loss from kidneys (e.g. excessive Addison’s disease) use of diuretics, corticosteroid Renal tubular disorders therapy) c. Excessive mobilisation from intracellular c. Excessive mobilisation from into extracellular compartment extracellular into intracellular Muscle necrosis (e.g. in crush compartment injuries, haemolysis) Excess insulin therapy Diabetic acidosis Alkalosis  Haemodynamic derangements The principles of blood flow are called haemodynamics. Normal circulatory function requires uninterrupted flow of blood from the left ventricle to the farthest capillaries in the body; return of blood from systemic capillary network into the right ventricle; and from the right ventricle to the farthest pulmonary capillaries and back to the left atrium. There are three essential requirements to maintain normal blood flow and perfusion of tissues: normal anatomic features, normal physiologic controls for blood flow, and normal biochemical composition of the blood. Derangements of blood flow or haemodynamic disturbances are considered under 2 broad headings: i. Disturbances in the volume of the circulating blood. These include: hyperaemia and congestion, haemorrhage and shock. ii. Circulatory disturbances of obstructive nature. These are: thrombosis, embolism, ischaemia and infarction.  Disturbances in the volume of circulating blood 1. Hyperaemia and congestion Hyperaemia and congestion are the terms used for localized increase in the volume of blood within dilated vessels of an organ or tissue; the increased volume from arterial and arteriolar dilatation being referred to as hyperaemia or active hyperaemia, whereas the impaired venous drainage is called venous congestion or passive hyperaemia. If the condition develops rapidly it is called acute, while more prolonged and gradual response is known as chronic. Active Hyperemia The dilatation of arteries, arterioles and capillaries is effected either through sympathetic neurogenic mechanism or via the release of vasoactive substances. The affected tissue or organ is pink or red in appearance (erythema). The examples of active hyperaemia are seen in the following conditions: Inflammation e.g. congested vessels in the walls of alveoli in pneumonia Blushing i.e. flushing of the skin of face in response to emotions Menopausal flush Muscular exercise High grade fever Clinically, hyperemia is characterized by redness and raised temperature in the affected part. Passive Hyperaemia (Venous Congestion) The dilatation of veins and capillaries due to impaired venous drainage results in passive hyperaemia or venous congestion, commonly referred to as congestion. Congestion may be acute or chronic, the latter being more common and called chronic venous congestion (CVC). The affected tissue or organ is bluish in colour due to accumulation of venous blood (cyanosis). Obstruction to the venous outflow may be local or systemic. Accordingly, venous congestion is of 2 types:  Local venous congestion  Systemic (General) venous congestion  Local venous congestion results from obstruction to the venous outflow from an organ or part of the body e.g. portal venous obstruction in cirrhosis of the liver, outside pressure on the vessel wall as occurs in tight bandage, plasters, tumours, pregnancy, hernia etc, or intraluminal occlusion by thrombosis.  Systemic (General) venous congestion is engorgement of systemic veins e.g. in left-sided and right-sided heart failure and diseases of the lungs which interfere with pulmonary blood flow like pulmonary fibrosis, emphysema etc. Usually the fluid accumulates upstream to the specific chamber of the heart which is initially affected. For example, in left-sided heart failure (such as due to mechanical overload in aortic stenosis, or due to weakened left ventricular wall as in myocardial infarction) pulmonary congestion results, whereas in right- sided heart failure (such as due to pulmonary stenosis or pulmonary hypertension) systemic venous congestion results.  Morphology of CVC of organs CVC lung Chronic venous congestion of the lung occurs in left heart failure, especially in rheumatic mitral stenosis so that there is consequent rise in pulmonary venous pressure. Grossly, the lungs are heavy and firm in consistency. The sectioned surface is dark The sectioned surface is rusty brown in colour referred to as brown induration of the lungs. Histologically, the alveolar septa are widened due to the presence of interstitial oedema as well as due to dilated and congested capillaries. The septa are mildly thickened due to slight increase in fibrous connective tissue. Rupture of dilated and congested capillaries may result in minute intra-alveolar haemorrhages. The breakdown of erythrocytes liberates haemosiderin pigment which is taken up by alveolar macrophages, so called heart failure cells, seen in the alveolar lumina. The brown induration observed on the cut surface of the lungs is due to the pigmentation and fibrosis. CVC Liver Chronic venous congestion of the liver occurs in right heart failure and sometimes due to occlusion of inferior vena cava and hepatic vein. Grossly, the liver is enlarged and tender and the capsule is tense. Cut surface shows characteristic nutmeg* appearance due to red and yellow mottled appearance, corresponding to congested centre of lobules and fatty peripheral zone respectively. Microscopically, the changes of congestion are more marked in the centrilobular zone due to severe hypoxia than in the peripheral zone. The central veins as well as the adjacent sinusoids are distended and filled with blood. The centrilobular hepatocytes undergo degenerative changes, and eventually centrilobular haemorrhagic necrosis may be seen. Long-standing cases may show fine centrilobular fibrosis and regeneration of hepatocytes, resulting in cardiac cirrhosis. The peripheral zone of the lobule is less severely affected by chronic hypoxia and shows some fatty change in the hepatocyte. 2. Haemorrhage Haemorrhage is the escape of blood from a blood vessel. The bleeding may occur externally, or internally into the serous cavities (e.g. haemothorax, haemoperitoneum, haemopericardium), or into a hollow viscus. Extravasation of blood into the tissues with resultant swelling is known as haematoma. Large extravasations of blood into the skin and mucous membranes are called ecchymoses. Purpuras are small areas of haemorrhages (upto 1 cm) into the skin and mucous membrane, whereas petechiae are minute pinhead-sized haemorrhages. Microscopic escape of erythrocytes into loose tissues may occur following marked congestion and is known as diapedesis. Etiology. The blood loss may be large and sudden (acute), or small repeated bleeds may occur over a period of time (chronic). The various causes of haemorrhage are as under: 1. Trauma to the vessel wall e.g. penetrating wound in the heart or great vessels, during labour etc. 2. Spontaneous haemorrhage e.g. rupture of an aneurysm, septicaemia, bleeding diathesis (such as purpura), acute leukaemias, pernicious anaemia, scurvy. 3. Inflammatory lesions of the vessel wall e.g. bleeding from chronic peptic ulcer, typhoid ulcers, blood vessels traversing a tuberculous cavity in the lung, syphilitic involvement of the aorta, polyarteritis nodosa. 4. Neoplastic invasion e.g. haemorrhage following vascular invasion in carcinoma of the tongue. 5. Vascular diseases e.g. atherosclerosis. 6. Elevated pressure within the vessels e.g. cerebral and retinal haemorrhage in systemic hypertension, severe haemorrhage from varicose veins due to high pressure in the veins of legs or oesophagus. Effects. The effects of blood loss depend upon 3 main factors:  the amount of blood loss;  the speed of blood loss; and  the site of haemorrhage. The loss up to 20% of blood volume suddenly or slowly generally has little clinical effects because of compensatory mechanisms. A sudden loss of 33% of blood volume may cause death, while loss of up to 50% of blood volume over a period of 24 hours may not be necessarily fatal. However, chronic blood loss generally produces iron deficiency anaemia, whereas acute haemorrhage may lead to serious immediate consequences such as hypovolaemic shock.  Shock Shock is a life-threatening clinical syndrome of cardiovascular collapse characterized by: an acute reduction of effective circulating blood volume (hypotension); and an inadequate perfusion of cells and tissues (hypoperfusion). If uncompensated, these mechanisms may lead to impaired cellular metabolism and death. Thus, by definition “true (or secondary) shock” is a circulatory imbalance between oxygen supply and oxygen requirements at the cellular level, and is also called as circulatory shock. The term “initial (or primary) shock” is used for transient and usually a benign vasovagal attack resulting from sudden reduction of venous return to the heart caused by neurogenic vasodilatation and consequent peripheral pooling of blood e.g. immediately following trauma, severe pain or emotional overreaction such as due to fear, sorrow or surprise. Clinically, patients of primary shock suffer from the attack lasting for a few seconds or minutes and develop brief unconsciousness, weakness, sinking sensation, pale and clammy limbs, weak and rapid pulse, and low blood pressure. Another type of shock which is not due to circulatory derangement is anaphylactic shock from type 1 immunologic reaction. In routine clinical practice, however, true shock is the form which occurs due to haemodynamic derangements with hypoperfusion of the cells; this is the type which is commonly referred to as ‘shock’ if not specified. Classification and Etiology Although in a given clinical case, two or more factors may be involved in causation of true shock, a simple etiologic classification of shock syndrome divides it into following 3 major types and a few other variants. 1. Hypovolemic shock. This form of shock results from inadequate circulatory blood volume by various etiologic factors that may be either from the loss of red cell mass and plasma from hemorrhage, or from the loss of plasma volume alone (Acute hemorrhage, dehydration from vomiting, diarrhea, burns and excessive use of diuretics) 2. Cardiogenic shock. Acute circulatory failure with sudden fall in cardiac output from acute diseases of the heart without actual reduction of blood volume (normovolaemia) results in cardiogenic shock. Deficient emptying e.g. (Myocardial infarction, cardiomyopathies, rupture of the heart, ventricle or papillary muscle, cardiac arrhythmias) Deficient filling e.g.(Cardiac tamponade from haemopericardium) Obstruction to the outflow e.g. (Pulmonary embolism, tension pneumothorax and dissecting aortic aneurysm) 3. Septic (Toxaemic) shock. Severe bacterial infections or septicaemia induce septic shock. It may be the result of Gram negative septicaemia (endotoxic shock) which is more common, or Gram- positive septicaemia (exotoxic shock). 4. Other types. These include following types: i. Traumatic shock. Shock resulting from trauma is initially due to hypovolaemia, but even after haemorrhage has been controlled, these patients continue to suffer loss of plasma volume into the interstitium of injured tissue and hence is considered separately in some descriptions (Severe injuries, surgery with marked blood loss and obstetrical trauma). ii. Neurogenic shock. Neurogenic shock results from causes of interruption of sympathetic vasomotor supply (Neurogenic shock, high cervical spinal cord injury, accidental high spinal anaesthesia and severe head injury) iii. Hypoadrenal shock. Hypoadrenal shock occurs from unknown adrenal insufficiency in which the patient fails to respond normally to the stress of trauma, surgery or illness. Administration of high doses of glucocorticoids and secondary adrenal insufficiency (e.g. in tuberculosis, metastatic disease, bilateral adrenal haemorrhage, idiopathic adrenal atrophy) Pathogenesis In general, all forms of shock involve following 3 derangements: Reduced effective circulating blood volume. Reduced supply of oxygen to the cells and tissues with resultant anoxia. Inflammatory mediators and toxins released from shock induced cellular injury. These derangements initially set in compensatory mechanisms but eventually a vicious cycle of cell injury and severe cellular dysfunction lead to breakdown of organ function. 1. Reduced effective circulating blood volume. It may result by either of the following mechanisms: a. by actual loss of blood volume as occurs in hypovolaemic shock; or b. by decreased cardiac output without actual loss of blood (normovolaemia) as occurs in cardiogenic shock and septic shock. 2. Impaired tissue oxygenation. Following reduction in the effective circulating blood volume from either of the above two mechanisms and from any of the etiologic agents, there is decreased venous return to the heart resulting in decreased cardiac output. This consequently causes reduced supply of oxygen to the organs and tissues and hence tissue anoxia, which sets in cellular injury. 3. Release of inflammatory mediators. In response to cellular injury, innate immunity of the body gets activated as a body defense mechanism and release inflammatory mediators but eventually these agents themselves become the cause of cell injury. Endotoxins in bacterial wall in septic shock stimulate massive release of pro-inflammatory mediators (cytokines) but a similar process of release of these agents takes place in late stages of shock from other causes. Several pro-inflammatory inflammatory mediators are released from monocytes-macrophages, other leucocytes and other body cells, the most important being the tumour necrosis factor- (TNF)-α and interleukin-1 (IL-1) cytokines. Pathophysiology (Stages of Shock) Although deterioration of the circulation in shock is a progressive and continuous phenomenon and compensatory mechanisms become progressively less effective, historically shock has been divided arbitrarily into 3 stages: 1. Compensated (non-progressive, initial, reversible) shock. 2. Progressive decompensated shock. 3. Irreversible decompensated shock. 42 Compensated (non-progressive, initial, reversible) shock. In the early stage of shock, an attempt is made to maintain adequate cerebral and coronary blood supply by redistribution of blood so that the vital organs (brain and heart) are adequately perfused and oxygenated. This is achieved by activation of various neurohormonal mechanisms causing widespread vasoconstriction and by fluid conservation by the kidney. If the condition that caused the shock is adequately treated, the compensatory mechanism may be able to bring about recovery and reestablish the normal circulation; this is called compensated or reversible shock. Progressive decompensated shock. This is a stage when the patient suffers from some other stress or risk factors (e.g. pre-existing cardiovascular and lung disease) besides persistence of the shock so that there is progressive deterioration. The effects of progressive decompensated shock due to tissue hypoperfusion are as under: i. Pulmonary hypoperfusion. Decompensated shock worsens pulmonary perfusion and increases vascular permeability resulting in tachypnoea and adult respiratory distress syndrome (ARDS). ii. Tissue ischaemia. Impaired tissue perfusion causes switch from aerobic to anaerobic glycolysis resulting in metabolic lactic acidosis. Lactic acidosis lowers the tissue pH which in turn makes the vasomotor response ineffective. This results in vasodilatation and peripheral pooling of blood. Clinically at this stage the patient develops confusion and worsening of renal function. Irreversible decompensated shock. When the shock is so severe that in spite of compensatory mechanisms and despite therapy and control of etiologic agent which caused the shock, no recovery takes place, it is called decompensated or irreversible shock. Clinical Features and Complications The classical features of decompensated shock are characterised by depression of 4 vital processes: Very low blood pressure Subnormal temperature Feeble and irregular pulse Shallow and sighing respiration In addition, the patients in shock have pale face, sunken eyes, weakness, cold and clammy skin.  Life-threatening complications in shock are due to hypoxic cell injury resulting in immuno- inflammatory responses and activation of various cascades (clotting, complement, kinin). These include the following*: Acute respiratory distress syndrome (ARDS) Disseminated intravascular coagulation (DIC) Acute renal failure (ARF) Multiple organ dysfunction syndrome (MODS) With progression of the condition, the patient may develop stupor, coma and death.