General Systemic State PDF

General Systemic state Sabry El-khodary 1 Presentation overview 1. Toxemia and endotoxemia 2. Septicemia and viremia 3. Alterations of body temperature (fever, Hyperthermia and hypothermia) 4. Shock 5. Pain 2 6. Disturbances of fluid, electrolytes and a...

General Systemic state Sabry El-khodary 1 Presentation overview 1. Toxemia and endotoxemia 2. Septicemia and viremia 3. Alterations of body temperature (fever, Hyperthermia and hypothermia) 4. Shock 5. Pain 2 6. Disturbances of fluid, electrolytes and acid-base imbalance 7. Disturbance of appetite 8. Shortfall performance SABRY EL-KHODERY Definition Toxemia is a clinical systemic state caused by widespread activation of host defense mechanisms to the presence of toxins in the blood stream produced by bacteria or injury to tissue cells. This state does not include the diseases caused by toxic substances produced by plants or insects or ingested organic or inorganic poisons. 3 The most common form of toxemia in large animals is endotoxemia, caused by the presence of lipopolysaccharide cell wall components of Gram-negative bacteria in the blood, and characterized clinically by abnormalities of many body systems. SABRY EL-KHODERY  The abnormalities of endotoxemia include: 1. Marked alterations in cardiopulmonary function. 2. Abnormalities in the leukon (neutropenia and lymphopenia) and thrombocytopenia that may lead to coagulopathies. 3. Increased vascular permeability. 4. Decreased organ blood flow and metabolism, leading to heart and renal failure. 4 5. Decreased gastrointestinal motility. 6. Decreased perfusion of peripheral tissues, leading to shock. 7. The need for intensive and complex therapy. 8. A high case fatality rate. SABRY EL-KHODERY Causes and types 5 SABRY EL-KHODERY  Antigenic toxins These are produced by bacteria and to less extent by helminth parasites acting as antigens and stimulate the development of antibodies. Exotoxins: These are protein substances produced by bacteria that diffuse into the surrounding medium. They may be ingested, as in botulism, or produced in large quantities by heavy growth in the intestines, such as in enterotoxemia, or from growth in tissue, as in blackleg and black disease. 6 The important bacterial exotoxins are those produced by Clostridium spp., for which commercial antitoxins are available. They are specific in their pharmacological effects and in the antibodies that they induce. SABRY EL-KHODERY  2. Enterotoxins:  These are exotoxins that exert their effect principally on the mucosa of the intestine, causing disturbances of fluid and electrolyte balance.  The most typical example is the enterotoxin released by enterotoxigenic E. coli, which causes a hyper-secretory diarrhea in neonatal farm animals. 3. Endotoxins:  The endotoxins of several species of Gram-negative bacteria are a major cause of morbidity and mortality in farm animals.  The endotoxins are lipopolysaccharides found in the outer wall 7 of the bacteria.  Endotoxins are released into the immediate surroundings when the bacteria undergo rapid proliferation with production of unused sections of bacterial cell wall or, most commonly, when the bacterial cell wall breaks. SABRY EL-KHODERY   Gram-negative bacteria are present in the intestinal tract as part of the normal microflora and endotoxins are also present. The endotoxins are not ordinarily absorbed through the intestinal mucosa unless it is injured, as in enteritis or more particularly in acute intestinal obstruction.  Ordinarily, small amounts of endotoxin that are absorbed into the circulation are detoxified in the liver but, if hepatic efficiency is reduced or the amounts of toxin are large, a state of endotoxemia is produced.  The most common causes of endotoxemia in horses are associated with diseases of the gastrointestinal tract including colitis, intestinal strangulation or obstruction and ileus.  Endotoxin gains access to the blood when there is a severe localized infection, such as a coliform mastitis in dairy cattle, or a disseminated 8 infection, such as coliform septicemia in newborn calves.  Endotoxins may also be absorbed in large amounts from sites other than intestine including the mammary gland, peritoneum, abscesses and other septic foci, or from large areas of injured or traumatized tissue. SABRY EL-KHODERY  B) Metabolic toxins  These may accumulate as a result of incomplete elimination of toxic materials normally produced by body metabolism, or by abnormal metabolism. Normally, toxic products produced in the alimentary tract or tissues are excreted in the urine and feces or detoxified in the plasma and liver.  When these normal mechanisms are disrupted, particularly in hepatic dysfunction (in liver diseases), the toxins may accumulate beyond a critical point and the syndrome of toxemia appears. 9  In obstruction of the lower alimentary tract, there may be increased absorption of toxic phenols, cresols and amines that are normally excreted with the feces, resulting in the development of the syndrome of autointoxication. SABRY EL-KHODERY   In ordinary circumstances in mono-gastric animals these products of protein putrefaction are not absorbed by the mucosa of the large intestine but when regurgitation into the small intestine occurs there may be rapid absorption, apparently because of the absence of a protective barrier in the wall of the small intestine.  The production of toxins by abnormal metabolism is taken to include the production of histamine and histamine-like substances in damaged tissues. 10 Ketonemia due to a disproportionate fat metabolism, and lactic acidemia caused by acute ruminal acidosis (grain overload), are two common examples of toxemia caused by abnormal metabolism. SABRY EL-KHODERY Pathogenesis 1. Effect on carbohydrate metabolism A fall in plasma glucose concentration, the rate and degree varying with the severity of endotoxemia. Disappearance of liver glycogen and decreased glucose tolerance of tissues so that administered glucose in not used rapidly. 11 Rise in the level of blood pyruvate, and lactate as a result of poor tissue perfusion and the anaerobic nature of tissue metabolism SABRY EL-KHODERY  2. Effect on protein metabolism Increase in tissue break down (catabolism) and a concomitant increase in serum urea nitrogen concentration. The changes observed include alterations in individual plasma amino acid concentrations, increased urinary nitrogen excretion and increased whole-body protein turnover. 12 Increase in total serum protein as result of increase antibody production. The globulins are increased and albumin decreased as part of the acute phase reaction. SABRY EL-KHODERY  3. Effect On Mineral Metabolism: Negative mineral balances occur  These include hypoferremia and hypozincemia as part of the acute phase reaction as the animal attempts to sequester these microminerals from invading bacteria.  Blood copper concentrations are commonly increased concurrently with an increase in blood ceruloplasmin levels. 13 SABRY EL-KHODERY  4. Effect On Cardiopulmonary function: The hemodynamic effects of endotoxemia are manifested in two phases.  In the early stages, heart rate and cardiac output commonly increased, although systemic blood pressure remains near or slightly less than normal. This is known as the hyper-dynamic phase of endotoxemia.  With uncontrolled endotoxemia, the hyper-dynamic phase progresses to the hypo-dynamic phase of shock. Changes include decreased cardiac output, systemic hypotension, 14 increased peripheral resistance and decreased central venous return. SABRY EL-KHODERY  5. Thermoregulation:  Bacterial endotoxins are potent stimulators of macrophage interleukins, which belong to a family of polypeptides functioning as key mediators of various infectious, inflammatory and immunological challenges to the host.  Interleukin-1 induces fever, an increase in the number and immaturity of circulating neutrophils, muscle proteolysis through increased prostaglandin E2 production, hepatic acute phase protein production, and reduced albumin synthesis.  Interleukin-l participates in the acute phase response, which is 15 characterized by fever, hepatic production of acute phase proteins, neutrophilia and pro-coagulant activity. SABRY EL-KHODERY  6. Effect On Body Organs:  The combined effects of the hypoglycemia, hyper L-Iactatemia and acidemia interfere with tissue enzyme activity and reduce the functional activity of most tissues.  The myocardium is weakened, the stroke volume decreases and the response to cardiac stimulants is diminished.  There is dilatation and in some cases damage to capillary 16 walls, so that the effective circulating blood volume is decreased; this decrease, in combination with diminished cardiac output, leads to a fall in blood pressure and the development of circulatory failure. SABRY EL-KHODERY   There is decreased liver function.  Damage to renal tubules and glomeruli causes a rise in blood non-protein nitrogen and the appearance of albuminuria.  The functional tone and motility of the alimentary tract is reduced and the appetite fails; digestion is impaired, with constipation usually following.  A similar loss of tone occurs in skeletal muscle and is 17 manifested by weakness and terminally by prostration.  There is a general depression of function attended by dullness, depression and finally coma. SABRY EL-KHODERY   Changes in the hemopoietic system include depression of hemopoiesis and an increase in the number of leukocytes - the type of cell that increases often varying with the type and severity of the toxemia. Leukopenia may occur but is usually associated with aplasia of the leukopoietic tissue associated with viruses or specific exogenous substances such as radioactive materials.  A secondary effect produced by some toxins is the creation of a state of hypersensitivity at the first infection so that a second 18 infection, or administration of the same antigen, causes anaphylaxis or an allergic phenomenon. SABRY EL-KHODERY  1. Acute toxemia Depression, anorexia and muscular weakness are common in acute endotoxemia. Calves do not suck voluntarily and may not have a suck reflex. Scant feces are common, but a low-volume diarrhea may also occur. The heart rate is increased. The pulse is weak and rapid but regular. 19 A fever is common in the early stages of endotoxemia but later the temperature may be normal or subnormal. Terminally, there is muscular weakness to the point of collapse and death occurs in a coma or with convulsions. SABRY EL-KHODERY  2. Endotoxemia  Endotoxemia is most commonly associated with bacteremia or septicemia due to infection with Gram-negative organisms, especially E. coli.  The clinical findings of severe endotoxemia include: 1. Depression. 2. Hyperthermia followed by hypothermia. 3. Tachycardia followed by decreased cardiac output. 4. Decreased systemic blood pressure. 5. Cool skin and extremities. 6. Diarrhea. 7. Congested mucosae with an increased capillary refill time. 8. Muscular weakness, leading to recumbency. 20 9. Renal failure is common and is characterized by anuria. 10. If DIC develops, it is characterized by petechial and ecchymotic hemorrhages on mucous membranes and sclera with a tendency to bleed from vein-puncture sites. SABRY EL-KHODERY   When toxin formation or liberation into the circulation is rapid and the toxicity of the toxin high enough, the onset of cardiovascular collapse is rapid enough to cause a state of 'toxic' or 'septic' shock. The remarkable clinical findings are: 1. Severe peripheral vasodilatation with a consequent fall in blood pressure. 2. Pallor of mucosa. 3. Hypothermia. 4. Tachycardia. 5. Pulse of small amplitude 6. Muscle weakness. 3. Chronic toxemia  Lethargy.  Separation from the group. 21  Inappetence.  Failure to grow or produce.  Emaciation are characteristic signs of chronic toxemia. SABRY EL-KHODERY 22 SABRY EL-KHODERY 23 SABRY EL-KHODERY   Leukocytosis and neutrophilia occur with mild endotoxemia and leukopenia, neutropenia and lymphopenia increase in severity and duration with increasing severity of endotoxemia.  A low plasma glucose concentration.  High serum urea concentration (non-protein nitrogen).  A low serum albumin and total protein concentration are usually present in acute endotoxemia in response to increased capillary permeability, whereas the azotemia reflects a decreased glomerular filtration rate.  A mild hypocalcaemia, hypomagnesaemia and hypokalemia, and hypophosphatemia, which most likely reflects inappetence and 24 decreased gastrointestinal tract motility.  In more chronic toxemic states, a high serum total protein concentration, with globulins, is more common. SABRY EL-KHODERY  The principles of treatment of endotoxemia or septic shock include 1. Removal of the foci of infection. 2. Administration of antimicrobial agents with a Gram-negative spectrum; Antimicrobial agents that alter the cell wall of Gram- negative bacteria can theoretically produce a bolus release of endotoxin when administered to animals with Gram negative septicemia. On this basis, β-lactam antibiotics effective against Gram 25 negative bacteria should theoretically be avoided, however, clinical experience has not indicated deleterious effects following administration of β-lactam antibiotics. Moreover, co- administration of aminoglycosides blocks the potential bolus release of endotoxin by β-lactam antibiotics. SABRY EL-KHODERY  3.Aggressive fluid and electrolyte therapy to combat the relative hypovolemia, hypoglycemia, and electrolyte and acid-base disturbances. Correction of peripheral vasoconstriction Restoration of an acceptable pulse quality Return of urine output Increase in the central venous pressure Restoration of mean arterial blood pressure to >65 mm Hg Restoration of cardiac output Restoration of oxygen delivery to acceptable levels 3. Non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids for the inhibition of products of the cyclooxygenase pathway; (NSAIDs) have 26 been in general use for the treatment of endotoxemia because of their analgesic, anti -inflammatory and antipyretic properties as Flunixin meglumine at 1.1-2.2 mg/kg BW/day intravenously for 5 days or Phenylbutazone given to calves at 5 mg/kg BW/day intravenously for 5 days.. SABRY EL-KHODERY  3.Glucocorticoids, improve capillary endothelial integrity and tissue perfusion, decrease activation of complement and the clotting cascade, decrease neutrophil aggregation, stabilize lysosomal membranes, protect against hepatic injury and improve survival rate. However, there are concerns about their use in septicemic animals because they may cause immunosuppression. 6.Inotropic agents and vasopressors, Inotropic agents increase cardiac contractility thereby increasing cardiac output and oxygen delivery. Vasopressor agents increase systemic arterial blood pressure. 27 A.Dobutamine (0.5-1.0 µg/kg BW/min in adults and 1-3 µg/kg BW/min in neonates) is the inotropic agent of choice. SABRY EL-KHODERY  A.Norepinephrine (0.01-1 µg/kg BW/min) is the vasopressor agent of choice in hypotensive animals that have not responded to intravenous fluid loading or dobutamine. 7.Antiserum, hyper-immune serum is commercially available for the treatment of endotoxemia in the horse. The rationale is that anti-lipid A antibodies bind circulating lipopolysaccharide, thereby preventing the subsequent inflammatory cascade. 28 8. Anticoagulants, disseminated intravascular coagulation (hyper-coagulable states) can be treated with heparin in an attempt to impair intravascular coagulation. SABRY EL-KHODERY  CONTROL OF ENDOTOXEMIA The hallmarks of a control program are to decrease the risk or prevent neonatal septicemia Institute early and aggressive treatment of gram-negative bacterial infections and ensure prompt surgical removal of ischemic and damaged intestine. Vaccines based on core lipopolysaccharide antigens are 29 widely used to decrease the incidence and severity of gram-negative mastitis in lactating dairy cows SABRY EL-KHODERY