Hematopoietic System Introduction: Introduction Blood supplies cells with water, electrolytes, nutrients, and hormones, and removes

waste products. The cellular elements supply oxygen (red blood cells), protect against foreign organisms and antigens (white cells), and initiate coagulation (platelets). Because of the diversity of the hematopoietic system, its diseases are best discussed from a functional perspective. Function may be classified as either normal responses to abnormal situations (eg, leukocytosis and left shift in response to inflammation) or primary abnormalities of the hematopoietic system (eg, pancytopenia from marrow failure). Furthermore, abnormalities may be quantitative (ie, too many or too few cells) or qualitative (ie, abnormalities in function). See also the immune system, Immunopathologic Mechanisms: Introduction et seq. Red Blood Cells The function of red blood cells (RBC) is to carry oxygen to the tissues at pressures sufficient to permit rapid diffusion of oxygen. This is done by a carrier molecule, hemoglobin (Hgb); a vehicle (RBC) capable of bringing the intact Hgb to the cellular level; and a metabolism geared to protect both the RBC and the Hgb from damage. Interference with synthesis or release of Hgb, production or survival of RBC, or metabolism causes disease. Hgb is a complex molecule, formed of four heme units attached to four globins (twoα and two βglobins). Iron is added in the last step by the ferrochelatase enzyme. Interference with the normal production of heme or globin leads to anemia. Causes include copper or iron deficiency and lead poisoning. Hemoglobinopathies such as thalassemias and sickle cell anemia, important genetic diseases of man, have not been seen in other animals. In these diseases, the production of globins (α or β, or both) does not balance heme production, and the Hgb is not functional. The only known hemoglobinopathy of animals is porphyria. Although described in several species, it is most important as a cause of photosensitivity in cattle (see Photosensitization: Introduction). Red cell mass, and thus oxygen-carrying capacity, remains constant over time in the normal animal. Mature RBC have a finite life span; their production and destruction must be carefully balanced, or disease ensues. Erythropoiesis is regulated by erythropoietin, which increases in the presence of hypoxia and regulates RBC production. In most species, the kidney is both the sensor organ and the major site of erythropoietin production, so chronic renal failure is associated with anemia. Erythropoietin acts on the marrow in concert with other humoral mediators to increase the number of stem cells entering RBC production, to shorten maturation time, and to cause early release of reticulocytes. Other factors that affect erythropoiesis are the supply of nutrients (such as iron, folate, or vitamin B12) and cell-cell interactions between erythroid precursors, lymphoid cells, and other components of the hematopoietic microenvironment. Factors that may suppress

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erythropoiesis include chronic debilitating diseases and endocrine disorders (such as hypothyroidism or hyperestrogenism). Two mechanisms exist for removal of senescent RBC; both conserve the principal constituents of the cell for reuse. Removal of aged RBC normally occurs by phagocytosis by the fixed macrophages of the spleen. As the RBC ages, it loses its flexibility due to impaired ATP production and becomes trapped in the spleen, unable to percolate through the splenic sinusoids. After phagocytosis and subsequent disruption of the cell membrane, Hgb is converted to heme and globin. Iron is released from the heme moiety and either stored in the macrophage as ferritin or hemosiderin, or released into the circulation for transport back to the marrow. The remaining heme is converted to bilirubin, which is released by the macrophages into the systemic circulation where it complexes with albumin for transport to the hepatocytes; there, it is conjugated and excreted into the bile. In extravascular hemolytic anemias, RBC have a shortened life span, and the same mechanisms occur at an increased rate. About 1% of normal aging RBC are hemolyzed in the circulation, and free Hgb is released. This is quickly converted to Hgb dimers that bind to haptoglobin and are transported to the liver, where they are metabolized in the same manner as are products from RBC removed by phagocytosis. In intravascular hemolytic anemia, more RBC are destroyed in the circulation (hemoglobinemia) than can be bound to haptoglobin. The excess Hgb and, therefore, iron are excreted in the urine (hemoglobinuria). The principal metabolic pathway of RBC is glycolysis, and the main energy source in most species is glucose. Glucose enters the RBC by an insulin-independent mechanism and most is metabolized to produce ATP and reduced nicotinamide adenine dinucleotide (NADH). The energy of ATP is used to maintain RBC membrane pumps so as to preserve shape and flexibility. The reducing potential of the NADH is utilized via the methemoglobin reductase pathway to maintain the iron in Hgb in its reduced form (Fe+2). The glucose not used in glycolysis is metabolized via a second pathway, the hexose monophosphate (HMP) shunt. No energy is produced via the HMP shunt; its principal effect is to maintain reducing potential in the form of reduced nicotinamide adenine dinucleotide phosphate (NADPH). In conjunction with the glutathione reductase/peroxidase system, NADPH maintains the sulfhydryl groups of globin in their reduced state. Some disorders are the direct result of abnormal RBC metabolism and interference with glycolysis. Inherited deficiency of pyruvate kinase, a key glycolytic enzyme, causes ATP deficiency, which leads to reduced RBC life span and hemolytic anemia. Excessive oxidant stress may overload the protective HMP shunt or methemoglobin reductase pathways and, thereby, cause Heinz body hemolysis or methemoglobin formation, respectively. Hemolytic anemias caused by certain drugs, such as phenothiazine in horses or acetaminophen in cats, are examples of this mechanism. See also anemia, Anemia of Chronic Disease , Chicken Anemia Virus Infection:
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Introduction , Equine Infectious Anemia: Introduction , Hemobartonellosis , Autoimmune Hemolytic Anemia and Thrombocytopenia . A decreased RBC mass (anemia) may be caused by blood loss, hemolysis, or decreased production. In acute blood loss anemia, RBC are lost, but mortality is usually related to loss of circulating volume, rather than to loss of RBC themselves. Iron is the limiting factor in chronic blood loss. Hemolysis may be caused by toxins, infectious agents, congenital abnormalities, or antibodies directed against RBC membrane antigens. Decreased RBC production may result from primary marrow diseases (such as aplastic anemia, hematopoietic malignancy, or myelofibrosis) or from other causes such as renal failure, drugs, toxins, or antibodies directed against RBC precursors. Malignancy of RBC or their precursors may be acute (eg, erythroleukemia) or chronic (eg, polycythemia vera). Animals with erythroleukemia are anemic despite having a marrow filled with rubriblasts, whereas those with polycythemia vera have erythrocytosis. White Blood Cells Phagocytes: The principal function of phagocytes is to defend against invading microorganisms by ingesting and destroying them, thus contributing to cellular inflammatory responses. There are two types of phagocytes: mononuclear phagocytes and granulocytes. Mononuclear phagocytes arise primarily from the marrow and are released into the blood as monocytes. They may circulate for hours to a few days before entering the tissues and differentiating to become macrophages. Granulocytes have a segmented nucleus and are classified according to their staining characteristics as neutrophils, eosinophils, or basophils. . Neutrophils circulate for only a few hours before travelling to the tissues. Five distinct stages in the process of phagocytosis have been identified: 1) attraction of phagocytes (chemotaxis) to microorganisms, antigen-antibody complexes, and other mediators of inflammation; 2) attachment to the organism; 3) ingestion; 4) fusion of cell lysosomes with ingested microorganisms and bacterial killing, and 5) digestion. In addition, many phagocytes have other specialized functions. Monocytes form a link to the specific immune system by processing antigen for presentation to lymphocytes and by producing substances like interleukin-1, which initiates fever and lymphocyte activation and stimulates early hematopoietic progenitors. Eosinophils, while having a role as phagocytes, also have more specific functions that include providing a defense against metazoan parasites and modulating the inflammatory process. They respond chemotactically to histamine, immune complexes, and eosinophil chemotactic factor of anaphylaxis, a substance released by degranulating mast cells. Basophils are not true phagocytes but contain large amounts of histamine as

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well as other mediators of inflammation. Both eosinophilia and basophilia may be seen in response to systemic allergic reactions and invasion of tissues by parasites. As with the RBC, the production and circulating numbers of phagocytes are tightly regulated and controlled by various humoral factors, including colony-stimulating factors and interleukins. Unlike the RBC, which remain circulating in the blood, the phagocytes use this compartment as a pathway to the tissues. Consequently, the number of phagocytes in the blood reflects circumstances in the tissues (eg, inflammation) as well as the proliferative function of the bone marrow. The sensitivity with which phagocytes reflect these conditions varies from species to species. Abnormal response such as neutropenia from marrow failure, infections, drugs, or toxins is likely to result in secondary bacterial infections. Finally, phagocyte precursors may undergo malignant transformation, which results in acute or chronic myelogenous leukemia. Lymphocytes: Lymphocytes are responsible for both humoral and cellular immunity. Cells of the two branches of the immune system cannot be differentiated morphologically, but they differ in their dynamics of production and circulation. Lymphocyte production in mammals originates in the bone marrow. Some of the lymphocytes destined to be involved in cellular immunity migrate to the thymus and differentiate further under the influence of thymic hormones. These become “T cells” and are responsible for a variety of helper, suppressor, or cytotoxic immunologic functions. Most circulating lymphocytes are T cells, but many are also present in the spleen and lymph nodes. The B cells migrate directly to organs without undergoing modification in the thymus and are responsible for humoral immunity (antibody production). Thus, lymphoid organs have populations of both B and T lymphocytes. In the lymph nodes, follicular centers are primarily B cells, and parafollicular zones are primarily T cells. In the spleen, most of the lymphocytes of the red pulp are B cells, whereas those of the periarteriolar lymphoid sheaths are T cells. Close association of T cells and B cells within lymphoid organs is essential to immune function. Lymphocyte function in the cellular immune system features both afferent (receptor) and efferent (effector) components. Long-lived T cells of the peripheral blood are the receptors. In response to antigens to which they have been previously sensitized, they leave the circulation and undergo blast transformation to form activated T cells, which in turn cause other T cells to undergo blast transformation, both locally and systemically. Stimulated T cells produce lymphokines with a wide range of activities, such as attraction and activation of neutrophils, macrophages, and lymphocytes. The humoral immune system is composed of B lymphocytes that produce antibodies of several classes. When sensitized B lymphocytes encounter antigen, they undergo blast transformation, divide, and differentiate into plasma cells that produce antibody. Therefore, each B lymphocyte initially stimulated produces a clone of plasma cells, all producing the same specific antibody.

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Antibody molecules (immunoglobulins) fall into several classes, each with its own functional characteristics. For example, IgA is the principal antibody of respiratory and intestinal secretions, IgM is the first antibody produced in response to a newly recognized antigen, IgG is the principal antibody of the circulating blood, and IgE is the principal antibody involved in allergic reactions. Antibodies perform their function by combining with the specific antigens that stimulated their production. Antigen-antibody complexes may be specifically chemotactic for phagocytes, or they may activate complement, a process that produces both cell lysis and substances chemotactic for neutrophils and macrophages. In this manner, the humoral immune system is related to, and interacts with, the nonspecific immune system. The humoral immune system also is related to both the nonspecific immune system and the cellular immune system in other ways. Both “helper” (CD 4) and “suppressor” (CD 8) T-cell classes have been described. Helper T cells are required for full expression of a humoral immune response. Suppressor T cells dampen the production of a given antibody. Natural killer cells, which are a class of lymphocyte distinct from T cells and B cells, destroy foreign cells (eg, neoplastic cells) even without prior sensitization. Antigen processing by macrophages precedes recognition of an antigen by lymphocytes. These complex processes are involved in routine surveillance against neoplastic cells and recognition of “self.” Lymphocyte response in disease may be appropriate (activation of the immune system) or inappropriate (immune-mediated disease and lymphoproliferative malignancies). See also immune system et seq. Immune-mediated disease results from failure of the immune system to recognize host tissues as self. For example, in immunemediated hemolytic anemia, antibodies are produced against the host's own RBC. Another inappropriate response of the immune system is allergy. In allergic individuals, IgE antibodies to allergens are bound to the surface of basophils and mast cells. When exposure to the allergen occurs, antigen-antibody complexes are formed, and degranulation of the mast cells and basophils releases vasoactive amines. Reaction to this may be mild (as in urticaria or atopy) or life-threatening (as in anaphylaxis). Lymphocytosis may occur in some species, especially the cat, as a response to epinephrine secretion. Atypical lymphocytes may be seen in the blood in response to antigenic stimulation (eg, vaccination). Persistent lymphocytosis in cattle infected with bovine leukemia virus is a benign polyclonal increase in lymphocyte numbers. Lymphoproliferative malignancies include lymphomas and acute lymphoblastic and chronic lymphocytic leukemias. Platelets Platelets form the initial hemostatic plug whenever hemorrhage occurs. They also are the source of phospholipid, which is needed for coagulation factors to interact to form a fibrin clot. Platelets are produced in the bone marrow from megakaryocytes,
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under the influence of thrombopoietin. Platelet production begins with invagination of the megakaryocyte cell membrane and the formation of cytoplasmic channels and islands. The cytoplasmic islands produce platelets by fragmentation from the megakaryocyte. Mature circulating platelets are packed with dense granules containing ATP, adenosine diphosphate (ADP), and calcium, as well as serotonin, lysosomes, glycogen, mitochondria, and an intracellular canalicular system. The mitochondria and glycogen are involved in energy production, and the canalicular system serves both as a transport system for granule components and as a source of phospholipid, which is found in high concentration in the membrane lining of the canals. When vessel walls are damaged, collagen and tissue factor are exposed, and circulating platelets adhere via von Willebrand factor and undergo a change in shape with the accompanying release of ADP. Local platelet aggregation is stimulated by ADP with the ultimate formation of the primary platelet plug. The local accumulation of fibrin and platelets is known as a hemostatic plug. The fibrin clot which then forms is consolidated by the action of platelet contractile proteins. Platelet disorders are either quantitative (thrombocytopenia or thrombocytosis) or qualitative (thrombocytopathy). Thrombocytopenia is one of the most common bleeding disorders of animals. In general, platelet counts must fall to <50,000/µL before the risk of hemorrhage increases. Consumption, destruction, or sequestration of platelets cause thrombocytopenia associated with increased production by the bone marrow. Consumptive thrombocytopenia occurs with massive hemorrhage or with disseminated intravascular coagulation, secondary to a variety of diseases. Destruction occurs in immune-mediated thrombocytopenia, in which platelets become coated with antiplatelet antibodies and are removed from the circulation by the fixed phagocyte system. Excessive sequestration of platelets by an enlarged spleen (hypersplenism) may occur in conditions such as myeloproliferative diseases and result in thrombocytopenia. (See also hemostatic disorders, Hemostatic Disorders: Introduction.) Decreased production of platelets in the marrow may be caused by drugs, toxins, or by primary marrow disorders such as aplasia, fibrosis, or hematopoietic malignancy. In primary marrow disorders, more than one hematopoietic cell line is often decreased, resulting in pancytopenia. Thrombocytosis occurs only rarely and is often idiopathic. It may be associated with primary marrow disease such as in megakaryocytic leukemia. Thrombocytosis is often associated with chronic blood loss and iron deficiency because of increased platelet production in the marrow reacting to continued consumption and loss. Thrombocytopathies comprise a poorly defined group of diseases in which platelet numbers are normal, but their function is impaired. Von Willebrand's disease is characterized by both a plasma coagulation defect and a defect in platelet adhesion to the endothelium. Other hereditary disorders of platelet function have been described but are relatively rare. Probably the most common platelet function defect results from
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aspirin administration, which irreversibly inhibits thromboxane (which is necessary for platelet aggregation). Anemia: Introduction Anemia is a condition characterized by insufficient circulating hemoglobin (Hgb). It results from excessive red blood cell (RBC) destruction, RBC loss, or decreased RBC production. Anemia is a manifestation of an underlying disease process; therefore, the response to treatment of an anemia is transient unless the underlying disease process is addressed. Classification of anemia can be helpful to generate a list of differential diagnoses in a given animal. Anemias can be regenerative or nonregenerative (Table: Classification of Anemias). Regenerative anemias show evidence of response by the bone marrow to increase the number of circulating RBC. This response is measured by the quantity of reticulocytes (immature RBC) present in the circulation. Regenerative anemias have a high reticulocyte count and are due to RBC loss or destruction. In a nonregenerative anemia, the bone marrow responds poorly and the reticulocyte count is low. Anemias can also be acute or chronic. Most commonly, acute anemias are due to either RBC loss or destruction. Chronic anemias are usually due to lack of RBC production, although slow blood loss can also be a cause. RBC indices are used to further characterize and classify anemias. The mean corpuscular volume (MCV) is an indication of RBC size. The MCV (femtoliters) = (PCV × 10) ÷ RBC (millions). As RBC precursors mature in the bone marrow, their volume decreases as the Hgb content increases. Therefore, reticulocytes have a higher MCV, and the MCV is increased in regenerative anemias. An anemia with a high MCV is classified as a macrocytic anemia. RBC size is smaller than normal when iron is insufficient, which results in decreased quantities of Hgb and a decreased MCV. An anemia with a low MCV is classified as a microcytic anemia. A low MCV in an anemic adult animal indicates iron deficiency from a slow loss of blood (usually GI or renal). A low MCV is seen in the Akita and Shiba Inu, which normally have small RBC. A low MCV may be seen in some cases of congenital hepatic shunts. The mean corpuscular hemoglobin concentration (MCHC) indicates the concentration of hemoglobin per unit volume of RBC. The MCHC (g/dL) = (Hgb × 100) ÷ PCV. It provides similar information as the mean corpuscular hemoglobin (MCH) but is considered to be more accurate. The MCH (picograms) = (Hgb × 10) ÷ RBC (millions). A low MCHC accompanying macrocytosis is indicative of a regenerative anemia. A low MCHC accompanying microcytosis is seen in iron deficiency. An increased MCHC indicates hemolysis or laboratory error. Laboratory diagnosis of anemia is based on the Hgb concentration, the number of RBC, and the hematocrit or packed cell volume (PCV). The next essential test is the reticulocyte count. Reticulocytes are polychromatic cells when stained with Wright's stain or a Giemsa-type stain. The vital stain new methylene blue specifically stains
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reticulocytes. Reticulocytosis is first seen 72 hr after the onset of significant blood loss or hemolysis. Peak reticulocyte response occurs within 5-7 days. Hemolysis usually results in a greater degree of reticulocytosis than does hemorrhage because the iron derived from RBC destruction is readily available to the bone marrow. The reticulocyte count is an indication of the degree of regeneration present and must be interpreted in light of the PCV. The reticulocyte index is a crude determination of whether the reticulocyte response is appropriate for the degree of anemia. The reticulocyte index = animal's PCV × % reticulocytes ÷ normal PCV. A value >1 indicates an appropriate response. Cats have a lesser degree of reticulocytosis for a specific level of anemia compared with dogs. Cats produce both aggregate and punctate reticulocytes. The aggregate reticulocytes are the polychromatic cells when stained with Wright's stain and are the only ones counted when determining the reticulocyte count. Evaluation of the marrow erythroid response is most accurate when blood is supravitally stained with new methylene blue, and reticulocytes are counted as a percentage of total RBC. Their absolute number should be determined to provide an answer that is independent of the degree of anemia. For example, in 1 µL of blood, a normal dog has 6.5 × 106 RBC with 1% (65,000) reticulocytes; an anemic dog may have 2 × 106 RBC with 3% (60,000) reticulocytes. Because the reticulocyte production of both dogs is nearly the same, the response of the anemic dog is poor. A good response is characterized by ≥3 × 105 reticulocytes/µL of blood, eg, 3 × 106 RBC with 10% reticulocytes. A simpler method of evaluating erythroid response is based on counting polychromatic RBC after Wright's or similar staining. The mean number of polychromatic RBC is determined for 10 oil-immersion fields over the length of the monolayer of the blood smear. A normal hemogram or an unresponsive anemia in the dog has 0-1 polychromatic RBC per field; mildly responsive anemias, 5 per field; moderately responsive anemias, 5-10 per field; and highly responsive anemias, 10-20 per field. Much lower numbers (about half that reported for dogs) are seen in cats, and no polychromasia (or reticulocytosis) is seen in horses. The cells/µL can be roughly estimated by multiplying the number of responsive cells per oil-immersion field (1,000×) by 8,000. Thus, if there is a mean of 10 polychromatic RBC per field, there are ~80,000/µL in the blood. Platelets may be enumerated in the same manner. This method consistently underestimates the response as compared with the reticulocyte count. See Table: Tsetse-transmitted Animal Trypanosomes for the normal ranges of RBC values for some domestic species.

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Examination of a peripheral blood smear is extremely useful for gaining information pertaining to regeneration and etiology of anemia. Spherocytes are seen in cases of immunemediated hemolytic anemia. They are not discernible in cats because feline RBC normally lack central pallor. Nucleated RBC in the presence of adequate reticulocytosis indicates regeneration. In the absence of a reticulocyte response however, they indicate bone marrow or splenic disease. The presence of Heinz bodies indicates a Heinz body anemia. Up to 10% of feline RBC normally contain Heinz bodies. Basophilic stippling and nucleated RBC may be seen in lead poisoning, and RBC agglutination indicates immune-mediated disease. Blood parasites may be seen in specific cases. Polychromatic cells are reticulocytes. Platelet numbers should be evaluated because thrombocytopenia may be seen in disseminated intravascular coagulopathy and in concurrent cases of immunemediated thrombocytopenia. Thrombocytosis and neutrophilia are often seen in cases of regenerative anemia. The PCV and total protein are determined simultaneously because a decrease in both values is seen in cases of blood loss anemia. A normal total protein and decrease in the PCV is seen with hemolysis and anemias due to lack of RBC production. The history and physical examination are extremely important because the underlying cause of anemia must be determined. Historical signs vary depending on whether the anemia is acute or chronic. Signs of acute anemia include sudden onset of weakness, lethargy, acute collapse, pale mucous membranes, change in urine color, tachypnea, and dyspnea. Usually, RBC loss or hemolysis is the cause. Signs of chronic anemia are often vague and include lethargy, depression, and anorexia. The owner may note pale mucous membranes, weakness, and dyspnea. In many instances, these signs may appear to be of sudden onset to the owner. Chronic anemias, characterized by a slower onset of signs, are usually nonregenerative and associated with decreased RBC production. In all cases, owners should be questioned about possible drug or toxin exposure, as well as the possibility of a traumatic incident. Owner complaints referable to a particular body system may localize the problem to this area. Findings of the physical examination are often determined by the duration of illness, the severity of blood loss, and the underlying disease process. Findings may include pale mucous membranes, increased cardiac and respiratory rates, heart murmur, weakness, shock with acute hemorrhage, petechiae or ecchymotic hemorrhages, icterus, melena, retinal hemorrhages, and splenomegaly. Severe pallor in a relatively strong animal indicates a slowly progressive anemia that is almost always nonregenerative. The history, physical examination, CBC, total protein, and reticulocyte count should indicate whether the anemia is attributable to blood loss (regenerative), increased RBC destruction (regenerative), or decreased RBC production (nonregenerative). Other appropriate diagnostic tests can then be performed (see Table: Diagnostic Tests for
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Blood Loss, Table: Diagnostic Tests for Increased RBC Destruction, and Table: Diagnostic Tests for Decreased RBC Production). Indications for a bone marrow biopsy include nonregenerative anemia, more than one cell line affected, selected neutropenias, selected thrombocytopenias, monoclonal gammopathy, and fever of unknown origin. Blood Loss Blood loss may be peracute, acute, or chronic, and the clinical signs depend on the rapidity of blood volume depletion. Chronic blood loss can result in iron deficiency, and a nonregenerative anemia develops. In peracute and acute hemmorhage, both the PCV and total protein are normal. It takes 6 hr for tissue fluids to re-expand the circulating blood volume, after which PVC and total protein decrease. Blood loss can be either external or internal. Internal blood loss usually results in a disproportionate decline in the PCV because proteins are readily reabsorbed into the blood vascular system while minimal amounts of intact RBC are reabsorbed. Significant reticulocytosis is absent unless 72 hr have elapsed from the beginning of the bleeding episode. External parasitism may cause anemia, particularly in young animals. In general, bloodsucking insects such as Tabanidae, black flies, and mosquitoes cause more irritation than blood loss. Calves occasionally become heavily infested with lice and become thin, weak, and mildly to severely anemic. Kittens and puppies can become severely anemic due to heavy flea or louse infestations. In endemic areas, bloodsucking ticks infest a wide variety of hosts. The animals should be treated with iron and application of ectoparasiticides. Transfusions are given if necessary. Cattle, especially, suffer marrow depression with heavy louse infestation, and recovery is slow. Internal parasitism also may cause anemia. Hookworm infection may cause profound anemia in young dogs and cats ( Hookworms). In severely affected animals that collapse, blood transfusions should precede anthelmintic treatment. Iron lost in intestinal parasitism is not reabsorbed; in chronic cases, response may be better to parenteral iron than to an anthelmintic. The marrow usually is productive if iron stores are not exhausted, and peripheral blood reticulocytosis is marked with occasional severe poikilocytosis. In sheep, acute haemonchosis ( Haemonchus, Ostertagia, and Trichostrongylus spp) may cause death due to anemia without debilitation. Diarrhea occurs with most GI parasitisms of sheep except Haemonchus . In calves and yearling cattle, chronic Ostertagia infection ( Haemonchus, Ostertagia, and Trichostrongylus spp) causes cachexia, an anemia with poor reticulocyte response, and occasionally marked poikilocytosis. Iron may be given parenterally if anemia is severe or serum iron is low. Neoplasms with bleeding into body cavities or tissue planes or external bleeding may cause a blood loss anemia that is often peracute in nature. Periodic episodes of weakness and anemia may result from rupturing tumors and a resultant small amount of blood loss. In these cases, a reticulocytosis is present because adequate time for regeneration has elapsed. A ruptured hematocyst or hematoma can appear exactly as a ruptured neoplasm.

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Initial treatment consists of volume expansion and RBC replacement when significant hemorrhage has occurred. Continued bleeding should be stopped, and the underlying disease condition treated. Excessive Rbc Destruction: Overview Hemolytic anemias may be extravascular or intravascular. Extravascular hemolysis occurs when the reticuloendothelial system phagocytizes RBC. Hgb is converted into bilirubin, resulting in icterus and bilirubinuria. When intravascular hemolysis occurs, RBC release Hgb into the blood vascular system, resulting in hemoglobinemia, hemoglobinuria, and, later, icterus. Direct and indirect bilirubin determinations are not extremely useful in hemolytic disease, except in the very early stages of disease. Indirect bilirubin has not yet been conjugated by the liver and is increased early on. The liver then conjugates bilirubin, and direct bilirubin levels rise. Because the liver can normally conjugate large amounts of bilirubin, a high indirect bilirubin in the presence of hemolytic disease and anemia indicates either severe hemolysis or concurrent liver disease. Extracorpuscular Abnormalities Immune-mediated Hemolytic Anemia (IHA): Immune-mediated hemolytic anemia is the accelerated destruction of RBC coated with antibody or antigen-antibody complexes adhered to the RBC surface. It is characterized by a regenerative anemia, spherocytosis (in dogs), and often the presence of autoantibodies against RBC (positive Coombs' test). Primary (idiopathic) IHA involves only the RBC themselves and accounts for 60-70% of cases in dogs. High concentrations of serum antibody to viral antigens in dogs with primary IHA suggest that idiopathic disease may follow viral infections. One study has provided clinical evidence for a temporal relationship of vaccine-associated IHA in dogs. Secondary IHA is associated with a wide variety of underlying conditions. These include immunemediated thrombocytopenia, systemic lupus erythematosus, viral disease, severe bacterial infection, granulomatous disease, lymphosarcoma, lymphocytic leukemia, and drug administration. Drugs associated with IHA include trimethoprim sulfa and ormetoprim sulfa in dogs and methimazole and propylthiouracil in cats. Clinical signs vary with the type of hemolysis and the onset of disease. In cases of complement-mediated intravascular hemolysis, the animal may present with a peracute onset of severe anemia, hemoglobinemia, hemoglobinuria, sudden weakness, collapse, and shock. Animals with acute or chronic disease involving extravascular hemolysis may present with weakness, fever, anemia, and possibly jaundice. Many animals have splenomegaly because the spleen is usually primarily involved in the RBC destruction. Laboratory findings also vary with the severity and type of RBC destruction. In peracute cases there is a lack of reticulocytosis. Later, a marked reticulocytosis is seen. Simultaneous bone marrow stimulation commonly results in a neutrophilic leukocytosis
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with a significant left shift. Serum bilirubin levels vary, as does the presence of hemoglobinuria and bilirubinuria. In some cases, RBC autoagglutinate when blood is placed in a collection tube containing anticoagulant. This must be confirmed microscopically to distinguish it from rouleaux formation, which is not a sign of immune-mediated RBC destruction. Therapy for IHA is directed toward suppressing destruction of RBC by the reticuloendothelial system and decreasing production of destructive antibody. In cases of secondary IHA, underlying causes must be recognized and treated. Immunosuppressive dosages of corticosteroids (prednisone 2.2 mg/kg or dexamethasone 0.3 mg/kg) are administered to rapidly suppress the reticuloendothelial system. These drugs are maintained at these levels until the PCV rises above 30 and then slowly tapered over a 2to 3-mo period. If corticosteroids are not effective, then other immunosuppressive drugs (eg, cyclophosphamide, azathioprine) are used. In addition to suppressing the reticuloendothelial system, these drugs decrease antibody production more rapidly than corticosteroids. These drugs are indicated in cases with severe autoagglutination, intravascular hemolysis, severe anemia most likely requiring transfusions, when a transfusion is administered, and when moderate to severe icterus is present. Other immunosuppressive drugs have been advocated, although no controlled studies have been done to demonstrate effectiveness. Recently, human immunoglobulin (0.5-1.5 g/kg, IV, over a 12-hr period) has been reported to be effective in dogs. Blood transfusions are given when clinical signs warrant. The use of transfusions ( Blood Groups And Blood Transfusions: Introduction) has not been related to increased mortality. If transfusions are done, crossmatching is essential, and the animal should be observed closely for reactions. Splenectomy has not been shown to be effective for IHA in dogs. Plasmapheresis can be extremely effective before cytotoxic therapy has had time to incur a beneficial response. However, it is available only at specific referral centers. Isoimmune Hemolytic Disease of the Neonate: This occurs when the fetus has a blood type that is incompatible with that of the mother who has been previously sensitized with RBC, resulting in production of isoantibodies. The newborn animal receives the antibodies when ingesting colostrum. Hemolytic Disease of Newborn Puppies and Kittens: Spontaneous sensitization of bitches and queens to fetal RBC antigens from puppies or kittens that share the major blood group antigens of their incompatible sires probably occurs more often than is realized. Of dogs, ~40% carry the DEA 1 antigen, and of cats, ~90% carry the A antigen. Therefore, the random chance of mating an animal carrying that antigen with an animal not carrying the antigen is 40:60 for dogs and 90:10 for cats. Diagnosis, management, and treatment of puppies or kittens affected with hemolytic disease follow the same principles discussed below for the large animal species. Hemolytic Disease of Newborn Calves: Spontaneous sensitization of cattle to fetal RBC antigens is rare or does not occur. Vaccines derived from blood and used to prevent babesiosis and anaplasmosis may
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contain RBC antigens that immunize the dams. If the bull has the same RBC antigens as the vaccine donor, then the calves may share these antigens and develop isoimmune hemolytic anemia when they receive colostrum. Gestation is normal. Antibody eluted from affected calf RBC has been shown to be an IgG and, at least in some cases, hemolytic. A single 2-mL dose of Babesia vaccine within a few weeks before calving may result in neonatal isoerythrolysis, and most fatal cases occur when dams have received 4-5 vaccinations within 1 yr. The Coombs' test usually is strongly positive. Owners may note red urine in newborn calves and exacerbate the problem by revaccinating dams on suspicion of neonatal infection. The disease may be mild or peracute with signs occurring 12-48 hr after birth. In peracute cases, death may occur as early as 2 hr after signs of severe dyspnea and 12-16 hr after birth. Acute cases are characterized by depression, dyspnea, and occasionally fever that develops 24-48 hr after birth. The calves continue to suck but weaken and have pallor that is masked in 1-2 days by mild to moderate jaundice. Death occurs at 4-5 days. Mildly affected calves show only dullness and reduced activity. In peracute cases, there is hemoglobinuria, hypofibrinogenemia, and high fibrin degradation products, with rapid death, a large spongy spleen, and discoloration of the kidneys. There is an excess of blood-stained pleural fluid, and the lungs are congested and edematous. In the acute form, the PCV drops to 6-7%, and often there is hemoglobinuria. The marrow is responsive but inadequate; 1-2% polychromatophilic RBC and up to 140 rubricytes per 100 WBC are seen. The Coombs' test is positive, the dam's milk agglutinates the calf's RBC, and hemolysis occurs if complement is added. In mild cases, the PCV drops to 18% at 1 wk after birth and rises to 30% by 3 wk. The anemia is normochromic and macrocytic. Diagnosis is usually made on clinical findings of a severe anemia in neonatal calves of dams that received a blood-origin vaccine. Confirmation is by agglutination of RBC of the sire and calf by colostrum and maternal serum. Blood usually is not transfused because of donor incompatability. A single transfusion from an unvaccinated cow, or transfusion of saline-washed (three times) packed RBC of the dam may be used to increase PCV to 25%. Antibiotics and steroids may be helpful. If suspected, the disease can be predicted by determining if cows have a titer against the RBC of the bull. When practical, colostrum from cows with no titer should be used until positive dams have been milked for 24-48 hr. Hemolytic Disease of Newborn Foals: Affected foals are normal at birth but can absorb dangerous amounts of isoantibodies from colostrum through their GI tract for up to 36 hr. Clinically recognizable neonatal isoerythrolysis rarely occurs in foals of primiparous mares and generally is not seen until a mare has had her third or fourth foal. Mares are isoimmunized naturally by focal placental breakdown, which permits fetal-placental hemorrhage of incompatible foal blood into the maternal circulation. A fairly large fetal-placental hemorrhage may be required to initially isoimmunize a mare to a significant degree. Restimulation of the
Circulatory System 13

mare in subsequent pregnancies requires much less incompatible foal blood of the same type. Also, therapeutic agents such as blood transfusions and incompatible tissue vaccines may contribute to the problem. Neonatal isoerythrolysis can occur only when a foal and its sire possess a blood factor absent in the mare. Certain stallions mated to sensitized mares always sire susceptible foals because they are genetically homozygous for the offending blood factor. Other stallions (heterozygotes) sire such foals only part of the time. Although neonatal erythrolysis may occur in foals of any breed, it is more frequent in Thoroughbreds and mules. The severity of anemia varies considerably, depending on the amount and type of isoantibodies consumed. Hemolytic isoantibodies are the most damaging, and the highest titers exist in the first colostrum; hence, vigorous foals that nurse heartily soon after birth may be affected the most severely. Signs may appear 8 hr to 5 days after birth. They include lethargy, jaundice, dyspnea, pounding heart, and in severe cases, hemoglobinuria. The foals spend much of their time lying down, and those severely affected often cannot stand. They nurse infrequently and only for short periods. The conjunctiva, sclera, and mucous membranes become progressively icteric in severely affected foals. RBC counts range from ~2 to 4 × 106/µL, and the RBC tend to autoagglutinate in their own plasma. Foals with RBC counts of this level during the first 24 hr require treatment. Diagnosis can be made clinically. A positive Coombs' test in an anemic foal is strong presumptive evidence, and demonstration of specific antibody against foal RBC in maternal serum or colostrum is definitive. Except for anemia, icterus, and sometimes hematuria, few lesions are regularly seen. Splenomegaly and generalized icterus are often seen in foals dying 24-48 hr after birth. For foals that are not severely affected, ordinary nursing care together with antibiotics and restriction of exercise for the first week usually result in recovery. Blood transfusion is the only known method of saving a severely anemic foal. The whole blood of the dam or the sire cannot be used in transfusions because it contains the hemolytic antibody, but the saline-washed RBC of the mare probably is the treatment of choice. A compatible donor is difficult to find; it should be selected for RBC that are not agglutinated or hemolyzed by the serum or colostrum of the mare and for serum that contains no demonstrable isoagglutinins or isohemolysins of the foal cells. The RBC count of the foal should be maintained at 3-4 × 106/µL, or the PCV at ≥15% until recovery. If the dam's RBC are available, two or three washes in isotonic saline solution are essential; ~2-3 L of mare's blood is sufficient. Alternatively, removal of 3-7 L of the foal's blood and replacement with 4-6 L of the donor's blood will correct the anemia and temporarily relieve the signs. Additional transfusions may be necessary, and supportive therapy is essential. Careful attention should be maintained to detect infection. Affected foals usually have a strong bone marrow response that is characterized by marked anisocytosis of RBC on blood smears and a shift in the MCV from 45-50 to 50-55 fL. Spherocytosis is also present but may be difficult to confirm. Polychromatic RBC are seldom found in peripheral blood, and their absence should be recognized as a species
Circulatory System 14

characteristic and not marrow failure. Occasionally, rubricytes as well as sideroleukocytes can be seen in severe cases. An accompanying neutrophilic leukocytosis is present. WBC counts increase to 15-25,000/µL with steroid treatment, which should be accompanied by antibiotic therapy. If the mare's serum shows a definite antibody titer (>1:2) near the end of gestation, or if a test of the mare's colostrum with the foal's cells at birth shows an antibody titer of >1:8, the disease can be avoided by separating the foal from its dam immediately at birth for 36 hr. The foal can be nursed by a normal foster mare or bottlefed on colostrum from nonimmunized mares. Such colostrum can be stored frozen for this purpose. The dam should be milked to remove most of her colostrum. The disease usually can be prevented by mating mares that have already produced one or more affected foals to stallions with RBC that are not agglutinated or hemolyzed by isoantibodies present in the mare's serum. However, in such cases, serum antibody levels should be measured during late gestation to detect the possible appearance of new isoantibodies. Hemolytic Disease of Newborn Piglets: Maternal sensitization can occur after use of a crystal-violet-inactivated hog cholera vaccine of blood origin or by natural transplacental sensitization. The spontaneous disease is primarily an isoimmune thrombocytopenia with lesser effects on the RBC. The piglets are normal at birth, and disease occurs after suckling. The first signs are due to RBC and platelet destruction in the peripheral blood. The marrow is responsive at first, and the disease is self-correcting for the first week. As antibody continues to be absorbed, marrow precursors are depressed, and the terminal petechiae are associated with decreased platelet production of marrow aplasia. The terminal anemia is due to both hemorrhage and hypoproliferation. Signs occur 1-4 days after birth and consist of pallor, inactivity, dyspnea, and jaundice. These signs gradually subside. After 10-11 days, multiple petechial hemorrhages develop over the ventral areas of the body; most piglets die at this time. The RBC count drops from a normal of 4.5-5.3 × 106/µL at birth to 1-3 × 106/µL at 4 days of age. As anemia develops, anisocytosis and polychromasia appear along with some circulating rubricytes. The MCV rises from a normal of 70 fL at birth to 100-120 fL at 1-2 wk of age and returns to normal in survivors 4 wk old. The neutrophils rise to 9-10 × 103 /µL at 4 days when RBC are lowest, and then decline to normal (3-4 × 103 /µL). Platelets have a bimodal response and drop from 300 × 103/µL) at birth to 100 × 103/µL at day 1, then rise to normal at the first week; however, severe thrombocytopenia follows after 10-14 days. In piglets that die, the bone marrow is hypoplastic and megakaryocytes are absent. RBC are Coombs' positive from day 1-7 and are negative by day 14. Usually, diagnosis is made on finding anemia, purpura, and mild icterus in neonatal pigs. The anemia is initially hemolytic, macrocytic, normochromic, and responsive; later, it becomes hypoplastic. Confirmation is by demonstration of agglutination of sire and piglet RBC and platelets by dam's serum and milk. Leptospirosis can be ruled out by demonstration of thrombocytopenia or by maternal titer.
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Treatment usually is not attempted; a substitute dam may be tried. Sows should not be rebred to the same sire after having affected litters. Hemolytic Anemia Due to Intravascular Fragmentation: Hemolysis has been associated with disseminated intravascular coagulopathy. The mechanism is believed to be physical fragmentation of RBC on intraluminal fibrin strands, and the damaged RBC are removed by the reticuloendothelial system. The anemia may be mild or severe and has been termed a microangiopathic hemolytic anemia. Schistocytes may be seen on a peripheral blood smear. Some of the disease conditions in which a microangiopathic hemolytic anemia has been recognized include heat stroke, transfusion reactions, shock, the postcaval syndrome seen with heartworm disease in dogs, neoplastic diseases (eg, hemangiosarcoma), hemolytic uremic syndrome in young calves, equine infectious anemia, African swine fever, and chronic hog cholera. Treatment is directed at the underlying disease process. Intracorpuscular Abnormalities Pyruvate kinase deficiency has been recognized in Basenjis, West Highland White Terriers, and Abbysinian cats. This enzyme is essential in energy production by the RBC, and its absence results in membrane changes that enhance phagocytosis by the reticuloendothelial system. The disease is transmitted as an autosomal recessive trait and is documented by assaying for pyruvate kinase activity. Carrier animals may also be detected by assaying for enzyme activity. A dramatic reticulocytosis is found, resulting in a macrocytic-hypochromic anemia. Spherocytes are absent. Late in the disease, myelofibrosis and osteosclerosis develop, which lead to decreased erythropoiesis, a nonregenerative anemia, and death. The average survival time is 2-3 yr. No definitive treatment is available. Splenectomy may be of help if performed early. Late in the disease, the spleen becomes a significant source of RBC production. Phosphofructokinase deficiency is seen in English Springer Spaniels and American Cocker Spaniels. It is characterized by intermittent bouts of hemolytic anemia associated with exertion and panting, which induce respiratory alkalosis and enhance RBC fragility. It is easily confused with immune-mediated hemolytic anemia. Therapy for acute anemia consists of calming the animal and providing supportive care, which may include transfusions. Prevention requires decreasing exertional activities. Lead poisoning ( Lead Poisoning: Introduction) may cause a mild to moderate, hypochromic, regenerative anemia. Excessive lead results in decreased RBC half-life and a reduction in heme synthesis. Increased numbers of nucleated RBC and reticulocytes are found. Basophilic stippling may be present. Diagnosis is confirmed by running a blood lead level. Therapy consists of elimination of lead from the GI tract, corticosteroids if cerebral edema develops, and drug administration to chelate lead and enhance its elimination from the body. Available drugs include Ca EDTA, penicillamine, and succimer.
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A hereditary nonspherocytic hemolytic anemia has been seen in Beagles and Poodles. Large numbers of reticulocytes are found. Osteosclerosis is common. Hereditary stomatocytosis associated with skeletal dwarfism has been recognized in Alaskan Malamutes. Blood Groups And Blood Transfusions: Introduction Blood groups are determined by genetically controlled, polymorphic, antigenic components of the RBC membrane. The allelic products of a particular genetic locus are classified as a blood group system. Some of these systems are highly complex with many alleles defined at a locus; others consist of a single defined antigen. Blood group systems, in general, are independent of each other, and their inheritance conforms to Mendelian dominance. For polymorphic blood group systems, an animal usually inherits one allele from each parent and thus expresses no more than two blood group antigens of a system. An exception is in cattle, in which multiple alleles or “phenogroups” are inherited. Normally, an individual does not have antibodies against any of the antigens present on its own RBC or against other blood group antigens of that species' systems unless they have been induced by transfusion, pregnancy, or immunization. In some species (man, sheep, cow, pig, horse, cat, and dog), so-called “naturally occurring” isoantibodies, not induced by transfusion or pregnancy, may be present in variable but detectable titers. For example, ~50% of dogs have a naturally occurring cold hemagglutinin, DEA 7. Also, circulating antibodies to animal blood group antigens may be induced by transfusion. With random blood transfusions in dogs, there is a 30-40% chance of sensitization of the recipient, primarily to blood group antigen DEA 1. In horses, transplacental immunization of the mare by an incompatible fetal antigen inherited from the sire may occur. Immunization also may result when some homologous blood products are used as vaccines (eg, anaplasmosis in cattle). The number of major recognized blood group systems (see Table: Major Blood Groups of Clinical Interest ) varies among domestic species with cattle being the most complex and cats the most simple. Animal blood groups are typed to aid in the matching of donors and recipients and to identify breeding pairs potentially at risk of causing hemolytic disease in their offspring. Because expression of blood group antigens is genetically controlled and the modes of inheritance are understood, these systems also can be used to substantiate pedigrees in cattle and horses. The increasing use of artificial insemination, cryopreservation, and embryo transfer has greatly expanded the application of these techniques. Blood typing of semen-donor bulls is widely practiced. Thoroughbred stallions, mares, and foals must be blood-typed before registration. Blood Typing Antisera used to identify blood groups (typing reagents) usually are produced as isoimmune sera. Their in vitro serologic characteristics vary with the species. Many reagents are hemagglutinins; others are hemolytic and require complement to complete the serologic reaction, such as in cattle because RBC do not readily agglutinate and in horses because RBC rouleaux are a problem. Other typing reagents, neither
Circulatory System 17

hemagglutinating nor hemolytic, combine with RBC antigens in an “incomplete” reaction because they lack additional combining sites to agglutinate other RBC; addition of species-specific antiglobulin is required for agglutination. Crossmatching The direct crossmatch procedure, with appropriate controls, is effective for all species. The major crossmatch detects antibodies already present in recipient plasma that could cause a hemolytic reaction when donor RBC are transfused; it will not detect the potential for sensitization to develop. Anticoagulant (EDTA or citrate) is added to blood samples from donor and recipient; the donor RBC are washed three times with 0.9% saline, and a 4% RBC suspension in saline is made from the washed cells. The major crossmatch consists of combining equal volumes (0.1 mL) of the donor RBC suspension and recipient plasma. The control tube contains recipient 4% RBC suspension and recipient plasma. The samples are incubated at 37°C for 15 min and then centrifuged at 1000 g for 15 sec. Hemolysis is evaluated by comparing the color of the supernatant in the test sample with that of the control sample. Each sample is then gently shaken until all cells in the “button” at the bottom of the tube have returned to suspension. Again, the degree of cell clumping of the test sample is compared with that of the control sample. The test is negative or compatible when the RBC are readily suspended. A positive or incompatible test can have hemolysis or hemagglutination, or both. All tests judged macroscopically to be negative for hemagglutination should be confirmed microscopically at low power. This is particularly important in horses because their RBC tend to form rouleaux. All negative tests should then be confirmed by an antiglobulin (Coombs') test: the RBC are washed three times with saline; an appropriate antiglobulin serum is added; and the sample is incubated for 15 min at 37°C, centrifuged at 1000 g, and checked for hemagglutination. The minor crossmatch is the reverse of the major crossmatch, ie, recipient cells are combined with donor plasma. The minor crossmatch is important only in species with naturally occurring isoantibodies or if the donor has been previously transfused or, in horses, previously pregnant. Blood Transfusions Frequently, the need for blood transfusions is acute, as in acute hemolysis or hemorrhage; transfusions are also appropriate in treatment of acute or chronic anemias. Animals with hemostatic disorders often require repeated transfusions of either whole blood, red cells, plasma, or platelets. Blood transfusions must be given with care because they have the potential for further compromising the recipient. The diversity of blood groups in animals and the lack of commercially available blood-typing reagents make complete typing and matching difficult but should not preclude the clinical use of transfusions. In horses and dogs, the blood group antigens most commonly implicated in transfusion incompatibilities are known; by selecting donor animals that lack these groups, the prevalence of recipient sensitization can be decreased. Previously sensitized recipients can be detected by crossmatching, which will preclude administration of incompatible blood. In the USA, >99% of cats are of blood group A, so the risk of
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incompatible transfusion is low. However, certain breeds, including Abyssinian, Birman, British Shorthair, Devon Rex, Himalayan, Persian, Scottish Fold, and Somali, have a higher frequency of blood group B. Any incompatible transfusion in cats results in rapid destruction of transfused cells. Whole blood frequently is not the ideal product to be administered. If the need is to replace the oxygen-carrying capability of the blood, then packed RBC are more appropriate; if replacement of circulatory volume is needed, crystalloid or colloid solutions may be used to replace volume, with packed RBC added as needed. Platelet numbers rise rapidly after hemorrhage, so replacement is not needed. Plasma proteins equilibrate from the interstitial space, so plasma is not needed except in massive hemorrhage (>1 blood volume in 24 hr). Animals that require coagulation factors benefit most from administration of fresh-frozen plasma or cryoprecipitate if the need is specifically for factor VIII, von Willebrands factor, or fibrinogen. Platelet-rich plasma or platelet concentrates may be of value in thrombocytopenia, although immune-mediated thrombocytopenia usually does not respond to administration of platelets because they are removed rapidly by the spleen. The amount of RBC to treat anemia is based on the volume necessary to increase the PCV or Hgb concentration to the desired value. All domestic animals have blood volumes of ~7% of their body weight except cats, which have a blood volume of 4% of their body weight. By determining the recipient's blood volume and knowing the animal's PCV, the required replacement RBC volume can be calculated. For example, a 25-kg dog has a total blood volume of ~2,000 mL; with a PCV of 15%, the RBC volume is 300 mL; if the PCV is to be increased to 20%, that equals an RBC volume of 400 mL. Therefore, 100 mL of RBC or 200 mL of whole blood (with PCV of 50%) would be required to increase the recipient's PCV to the desired level. These calculations assume no ongoing losses of RBC through hemorrhage or hemolysis. No more than 25% of a donor animal's blood should be collected at one time. Collection, storage, and transfusion of blood must be done aseptically. The anticoagulant of choice is citrate phosphate dextrose adenine (CPDA-1). Commercial blood bags containing the appropriate amount of anticoagulant are less damaging to blood cells than are vacuum collection bottles. Heparin should not be used as an anticoagulant because it has a longer half-life in the recipient and causes platelet activation; also, heparinized blood cannot be stored. Blood collected in CPDA-1 may be safely stored at 4°C for 3 wk. If the blood will not be used immediately, the plasma can be removed and stored frozen for later use as a source of coagulation factors or albumin for acute reversible hypoalbuminemia. Chronic hypoproteinemia is not helped by plasma because the total body deficit of albumin is so large that it could not be improved by the small amount contained in plasma. Plasma must be frozen at -20° to -30°C within 6 hr of collection to assure that levels of factor VIII are adequate and will remain so for 1 yr. Risks of Transfusion:
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The most serious risk of transfusion is acute hemolysis. Fortunately, this is rare in domestic animals. Dogs rarely have clinically significant preformed antibodies, so only those that have received repeated transfusions are at risk. The most common hemolytic reaction in dogs that have received multiple transfusions is delayed hemolysis, seen clinically as shortened survival of transfused RBC and a positive Coombs' test. Even crossmatch-compatible RBC given to horses or cattle survive only 2-4 days. Repeated transfusions can cause acute hemolysis. Nonimmune causes of hemolysis include improper collection or separation of blood, freezing or overwarming of RBC, and infusing under pressure through a small needle. Other complications include sepsis from contaminated blood, hypocalcemia from too much citrate, and hypervolemia (especially in animals with preexisting heart disease or in very small animals). Urticaria, fever, or vomiting are seen occasionally. Transfusions can also spread disease from donor to recipient, such as RBC parasites (eg, Haemobartonella , Anaplasma , or Babesia ) and viruses (eg, retroviruses such as feline or bovine leukemia, equine infectious anemia, or other slow viruses). Other diseases, such as those caused by rickettsia or other bacteria, can also be spread if the donor is bacteremic. Blood Substitutes An ideal blood substitute would pick up and deliver oxygen and be isosmotic, nonantigenic, inexpensive, nontoxic, incapable of transmitting infections, and have a half-life of at least several days. Although the ideal blood substitute has yet to be developed, progress is being made, especially in development of stroma-free hemoglobin solutions. Purified polymerized hemoglobin solutions of bovine or human origin are being investigated. Fluorocarbon solutions have also been undergoing testing for many years, but continued problems with efficacy and safety have slowed development. Anaplasmosis Anaplasmosis, formerly known as gall sickness, is a disease of ruminants caused by obligate intraerythrocytic parasites of the order Rickettsiales, family Anaplasmataceae, genus Anaplasma . Cattle, sheep, goats, deer, antelope, giraffes, and buffalo may be infected. Bovine anaplasmosis is of economic significance in the cattle industry and is the focus of this discussion. Anaplasmosis occurs in tropical and subtropical regions worldwide (~ 40° N to 32° S), including South and Central America, the USA, southern Europe, Africa, Asia, and Australia. Etiology: Clinical bovine anaplasmosis is usually caused by A marginale . Cattle are also infected with A caudatum , which may result in severe disease, and A centrale , which generally results in mild disease. Anaplasma ovis may cause mild to severe disease in sheep, deer, and goats.
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Transmission and Epidemiology: Anaplasmosis is not contagious. Most transmission occurs via numerous species of tick vectors. At least 16 species of ticks of 7 genera ( Boophilus , Dermacentor , Rhipicephalus , Ixodes , Hyalomma , Argas , and Ornithodoros ) have been shown experimentally to transmit A marginale . Not all of these are likely to be significant vectors in the field. Boophilus species are major vectors in Australia and Africa, and Dermacentor species have been incriminated as the main vectors in the USA. After feeding on an infected animal, intrastadial or trans-stadial transmission may occur. Transovarial transmission may also occur, although this is rare, even in the one-host Boophilus species. A replicative cycle occurs in the infected tick. Mechanical transmission via biting dipterans occurs in some regions. Transplacental transmission has been reported and is usually associated with acute infection of the dam in the second or third trimester of gestation. Anaplasmosis may also be spread through the use of contaminated needles or dehorning or other surgical instruments. There is a strong correlation between age of cattle and severity of disease. Calves are much more resistant to disease (though not infection) than older cattle. This resistance is not due to colostral antibody from immune dams. In endemic areas where cattle first become infected with A marginale early in life, losses due to anaplasmosis are minimal. After recovery from the acute phase of infection, cattle remain chronically infected carriers of the parasite and immune to further clinical disease. However, these chronically infected cattle may relapse to anaplasmosis when immunosuppressed (eg, by corticosteroids), when infected with other parasites, or after splenectomy. Carriers serve as a reservoir for further transmission. Serious losses due to anaplasmosis occur when mature cattle with no previous exposure are moved into endemic areas or under endemically unstable situations when transmission rates are insufficient to ensure all cattle are infected before reaching the more susceptible adult age. Clinical Findings: Anaplasmosis is characterized by progressive anemia due to extravascular destruction of infected and uninfected erythrocytes. The prepatent period of A marginale is directly related to the infective dose and typically ranges from 2 to 8 wk. Parasitemia approximately doubles every 24 hr during the exponential growth phase. Generally, 1030% of erythrocytes are infected at peak parasitemia, although this figure may be as high as 65%. Erythrocyte count, PCV, and hemoglobin values are all severely reduced. Macrocytic anemia with circulating reticulocytes may be present late in the disease. There is moderate anisocytosis, slight polychromasia, and an increase in unconjugated bilirubin in the serum. Acutely infected animals lose condition rapidly. Milk production falls. Inappetence, loss of coordination, breathlessness when exerted, and a rapid bounding pulse are usually evident in the late stages. The urine may be brown but, in contrast to babesiosis, hemoglobinuria does not occur. A transient febrile response, with the temperature rarely exceeding (106°F) occurs at about the time of peak parasitemia. Mucous membranes
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appear pale and then yellow. Pregnant cows may abort. Surviving cattle convalesce over several weeks, during which hematologic parameters gradually return to normal. There is no clear evidence that Bos indicus cattle are any more resistant to infection than B taurus breeds. Lesions: The carcasses of cattle that die from anaplasmosis are generally markedly anemic and jaundiced. Blood is thin and watery. The spleen is characteristically enlarged and soft, with prominent follicles. The liver may be mottled and yellow-orange. The gallbladder is often distended and contains thick brown or green bile. Hepatic and mediastinal lymph nodes appear brown. Epicardial and pericardial petechiae and ecchymoses are often present. Widespread phagocytosis of erythrocytes is evident on microscopical examination of the reticuloendothelial organs. A significant proportion of erythrocytes are usually found to be parasitized after death due to acute infection. Diagnosis: Anaplasma marginale , together with the hemoprotozoa Babesia bovis and B bigemina , are the causative agents of tick fever in cattle. These three parasite species have similar geographic distributions, except that anaplasmosis occurs in the absence of babesiosis in the USA. Microscopical examination of Giemsa-stained thin and thick blood films is critical to distinguish anaplasmosis from babesiosis and other conditions that result in anemia and jaundice, such as leptospirosis and theileriosis. Blood in anticoagulant should also be obtained for hematologic testing. In Giemsa-stained thin blood films, Anaplasma spp appear as dense, homogeneously staining blue-purple inclusions 0.3-1.0 µm in diameter. Anaplasma marginale inclusions are usually located toward the margin of the infected erythrocyte, whereas A centrale inclusion bodies are located more centrally. Anaplasma caudatum cannot be distinguished from A marginale using Giemsa-stained blood films. Special staining techniques are used to identify this species based on observation of characteristic appendages associated with the parasite. Inclusion bodies contain between 1 and 8 initial bodies 0.3-0.4 µm in diameter, which are the individual rickettsia. Chronically infected carriers may be identified with a fair degree of accuracy by serologic testing using either complement fixation or card agglutination tests Experimental DNA-based detection methods have been reported but are not yet in general use. At necropsy, thin blood films of liver, kidney, spleen, lungs, and peripheral blood should be prepared for microscopical examination. Treatment: The tetracyclines and imidocarb are currently used for treatment. Cattle may be sterilized by treatment with these drugs and remain immune to severe anaplasmosis subsequently for at least 8 mo. Prompt administration of tetracycline, chlortetracycline, or oxytetracycline in the early stages of acute disease (eg, PCV >15%) usually ensures survival. A commonly used treatment consists of a single IM injection of long-acting oxytetracycline at 20
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mg/kg. Blood transfusion to partially restore the PCV greatly improves the survival rate of more severely affected cattle. The carrier state may be eliminated by administration of a long-acting oxytetracycline preparation (20 mg/kg, IM), at least two injections with a 1-wk interval. Withholding periods for tetracyclines apply in most countries. Injection into the neck muscle rather than the rump is preferred. Imidocarb is also highly efficacious against A marginale as a single injection (as the dihydrochloride salt at 1.5 mg/kg, SC, or as imidocarb dipropionate at 3.0 mg/kg). Elimination of the carrier state requires the use of higher repeated doses of imidocarb (eg, 5 mg/kg, IM or SC, two injections of the dihydrochloride salt 2 wk apart). Imidocarb is a suspected carcinogen with long withholding periods and is not approved for use in the USA or Europe. Prevention: In some countries, infection with live A centrale is used as a vaccine to protect cattle against severe disease due to subsequent infection with the more pathogenic species A marginale . Anaplasma centrale vaccine produces severe reactions in a small proportion of cattle. In the USA, where use of A centrale vaccine cannot be used, a vaccine comprising nonliving A marginale purified from infected bovine erythrocytes is available. Immunity generated using this killed vaccine protects cattle from severe disease on subsequent infection. Instances of isoerythrolysis in suckling calves have occurred due to prior vaccination of dams with preparations of this vaccine that contained bovine erythrocytic material. Long-lasting immunity against A marginale is conferred by preimmunization with the live parasite, combined with the use of chemotherapy to control severe reactions. The use of attenuated strains of A marginale as a live vaccine has been reported. In some areas, sustained stringent control or elimination of the arthropod vectors may be a viable control strategy. Hemobartonellosis (Feline infectious anemia) Feline infectious anemia (FIA) is an acute or chronic disease of domestic cats, seen in many parts of the world, caused by a rickettsial agent that multiplies within the vascular system. Etiology, Transmission, and Pathogenesis: FIA is caused by an epicellular RBC rickettsial parasite, Haemobartonella felis (termed Eperythrozoon felis in Europe and Australia). It is gram-negative and nonacidfast and reproduces by binary fission. In blood smears, H felis typically appear as cocci in thick areas of the film and as rings or rods in thin areas. The dimensions vary from 0.2 to 1 mm in diameter for the coccoid forms and up to 3 mm in length for the rod forms. The causative organisms are usually found in varying numbers on the surface of the RBC but are occasionally seen free in the plasma. They appear as dark red-violet bodies in thin blood smears stained with Wright-Giemsa stain or as purple to blue organisms attached to RBC when using the May-Grunwald-Giemsa staining procedure; this procedure appears to be superior to other Romanowsky staining techniques. Acridine orange staining and direct immunofluorescence techniques have also been recommended
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for diagnosis of H felis ; unfortunately, these techniques require special equipment and training and are not commercially available. The number of RBC affected varies with the severity of the infection and the stage in the life cycle of the parasite. Blood films should be examined daily for 5-10 days if infection with H felis is suspected because organisms are recognized in only 50% of cats in the acute phase of the disease. During the acute phase, numbers of H felis organisms increase gradually, then disappear rapidly; clearance of organisms may occur within 2 hrs. In chronically infected cats, organisms appear only sporadically and in small numbers. FIA can be transmitted experimentally by parenteral or oral transfer of small amounts of infected whole blood into susceptible cats. Intrauterine transmission can also occur, and infections can be transmitted iatrogenically via blood transfusions. However, the natural mode of transmission is believed to be via blood-sucking arthropods (such as fleas) and possibly via bite wounds. In experimental cases, the incubation period is 1-5 wk, and recovery does not induce immunity to reinfection. Incidence of the naturally occurring disease appears to be higher among 1- to 3-yr-old cats, particularly males. A significant portion of the feline population may carry the infection in a latent form, which becomes exacerbated during debilitating disease or stress. Underlying infection with feline leukemia or feline immunodeficiency virus should always be investigated in cats with hemobartonellosis. It is thought that H felis may not cause illness in healthy cats, but that it leads to acute disease only when an infected cat is stressed by concurrent illness. Similarly, recovered carrier cats are believed to be prone to relapse with stress. Immune-mediated mechanisms of RBC injury are also important in the pathogenesis of FIA. Parasitized RBC may be damaged by antibody-complement interactions against H felis antigens. In addition, parasite-induced exposure of hidden or altered RBC antigens may lead to RBC destruction; erythrophagocytosis by the reticuloendothelial system appears to be more important than intravascular hemolysis. In experimental infection, the Coombs' test becomes positive 7-14 days after organisms appear in the blood and remains positive throughout the acute phase; the Coombs' test becomes negative during the carrier phase of the disease. Clinical Findings: Any anemic cat may be suspected of having FIA. In acute cases, there is usually a fever of 103-106°F (39-41°C); the temperature may drop to subnormal in moribund cats. Experimentally, cats have two or more parasitemic episodes before the resulting anemia leads to clinical signs. The severity of clinical signs correlates with the rapidity of onset of anemia. Pallor or jaundice, anorexia, lethargy, depression, weakness, and splenomegaly are common clinical signs. In chronic or slowly developing cases, there may be normal or subnormal temperature, weakness, depression, and weight loss or emaciation, but there is less likely to be jaundice and splenomegaly. Dyspnea varies with the degree of anemia. Gross necropsy findings are not pathognomonic;
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splenomegaly is common, and mesenteric lymph nodes may be enlarged. Hyperplasia of the bone marrow may be present. Diagnosis: Laboratory confirmation depends on identification of the parasite in the peripheral blood or bone marrow. A series of smears stained with Wright-Giemsa stain over a period of several days may be required for an accurate diagnosis because the erythrocytic bodies exhibit periodicity. Certain artifacts such as Howell-Jolly bodies may be mistaken for blood parasites. The slides should be clean, and the stains should be filtered immediately before use because dirt particles and stain precipitates can mimic the appearance of the organism. In the southeastern USA, differentiation from feline cytauxzoonosis ( Cytauxzoonosis) should be made. Cytauxzoon felis appears as an intracellular ring, rod, or coccoid-shaped protozoan 0.5-2 mm in diameter within RBC, while H felis tends to form chains on the surface of RBC. Expected laboratory abnormalities include a regenerative anemia; typical changes include diffuse basophilic granules in larger erythrocytes, nucleated RBC, polychromasia, anisocytosis, Howell-Jolly bodies, and an increased reticulocyte count. However, if the onset of anemia is rapid, a nonregenerative anemia may be present. Red blood cell counts may fall as low as 1 ×10 6/µL, and hemoglobin values of ≤7 g/dL may be seen. Mean corpuscular volume may be increased. There may be moderate leukocytosis with monocytosis in acute forms, normal counts in chronic forms, and leukopenia in moribund cases. Erythrophagocytosis and autoagglutination may be present in peripheral blood. Serum biochemical changes often include increased ALT, AST, bilirubin, and total protein levels; moribund cats may be hypoglycemic. Treatment: Treatment involves both supportive and specific therapies. Without treatment, onethird of acutely ill cats may die. Severely dyspneic cats may require oxygen, and whole blood or packed RBC transfusions may be needed in cats with a PCV of ≤15%, particularly if the anemia is acute. The decision to transfuse should be based on the cat's clinical condition rather than on the PCV. Tetracycline (20 mg/kg, PO, t.i.d. for 21 days) is recommended as a specific antirickettsial agent. Doxycycline (10 mg/kg, PO, s.i.d. for 21 days) is also effective. Unfortunately, H felis is not completely eliminated by tetracycline therapy, resulting in chronically infected carrier animals. Thiacetarsamide sodium (1 mg/kg, IV, every 48 hr for two treatments) has also been recommended for the treatment of hemobartonellosis; however, recent reports have suggested that this agent is less effective than previously thought. Although chloramphenicol has also shown efficacy against H felis , it can cause a significant but reversible erythroid hypoplasia that may interfere with the regenerative response. The use of glucocorticoids is recommended based on the evidence of immunemediated RBC injury. Prednisone or prednisolone (2-4 mg/kg, PO, s.i.d.) should be used
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in conjunction with antibiotic therapy, and the dose should be gradually tapered as the PCV increases. Canine Malignant Lymphoma: Introduction (Lymphoma, Lymphosarcoma, Lymphocytic leukemia) Canine malignant lymphoma is a progressive, fatal disease characterized by neoplastic transformation and proliferation of lymphoid cells, usually originating in solid lymphoid organs (lymphosarcoma) or bone marrow (lymphocytic leukemia). The variable signs depend on which organs are involved. No viral etiology has been established in dogs, in contrast to most other domestic species. The disease is histologically and immunologically heterogeneous, and different morphologic subtypes may behave differently. It is the most common hematopoietic neoplasm of dogs (reported incidence 24:100,000). All breeds and both sexes are affected, although the incidence is higher in Boxers, Golden Retrievers, and Old English Sheepdogs. Clinical Findings: The most common early clinical sign is a painless, peripheral lymphadenopathy, often first noticed in lymph nodes about the throat and neck. Subsequently, nonspecific signs, including anorexia, weight loss, anemia, and inactivity develop gradually as neoplastic cells progressively infiltrate visceral organs. In the alimentary form, signs are associated with GI obstruction or malabsorption; 80% of affected dogs may have diarrhea and weight loss. Other less common types include an anterior mediastinal form with primary involvement of the area of the thymus, an epitheliotropic form (mycosis fungoides), and extranodal (atypical) forms that involve a single organ such as the kidney. Hypercalcemia may be seen in 10-40% of dogs with malignant lymphoma. There are two general mechanisms: one is local elaboration of an osteolytic factor that induces resorption of bone and mobilization of calcium when the bone marrow is infiltrated by tumor cells; the other, probably more common, is humoral hypercalcemia in which neoplastic cells produce a substance that acts at a distance (see also hypercalcemia of malignancy, Hypercalcemia of Malignancy ). In both cases, it appears that a boneresorbing substance is produced that is immunologically distinct from parathyroid hormone, prostaglandin E2, and 1,25-dihydroxycholecalciferol. Dogs with hypercalcemia have polyuria and polydipsia or renal failure. Urinary excretion of calcium, phosphorus, and hydroxyproline is increased if there is hypercalcemia. Untreated dogs usually die within 1-2 mo of diagnosis. Lesions: Commonly, all superficial and various internal lymph nodes are 3-10 times normal size (multicentric form). Affected nodes are freely movable, firm, and gray-tan; they bulge on cut surface and have no cortical-medullary demarcation. Frequently, there is hepatosplenomegaly with either diffuse enlargement or multiple, pale nodules of variable size disseminated in the parenchyma. Involvement of the bone marrow, GI tract, kidney, heart, tonsils, pancreas, and eyes can occur but is less common. In the
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alimentary form, the second most common form of the disease, any part of the GI tract or mesenteric lymph nodes may be affected, but superficial lymph nodes and the spleen are rarely involved. Diagnosis: True lymphocytic leukemia, which is characterized by a normal to increased WBC count with a predominance of lymphoid cells in peripheral blood and bone marrow is rare and must be differentiated from lymphosarcoma because of the different prognosis and response to therapy. Poorly differentiated, acute lymphoblastic leukemia is an aggressive disease with a poor prognosis, whereas well-differentiated, chronic lymphocytic leukemia is slowly progressive and responds relatively well to therapy. Frequently, there is a diffuse splenomegaly. Most dogs with lymphosarcoma have a normal hematologic profile. In the later stages, an absolute neutrophilia may develop. Most canine lymphomas are high-grade (blast cell), diffuse lymphosarcomas, although ~20% are low-grade (well-differentiated). Dogs with high-grade tumors respond better to chemotherapy and have longer remission and survival times than those with low-grade lymphomas, which may have a more indolent course and do not respond as well to chemotherapy. The cell of origin is either the B- or T-cell lymphocyte, although some are of undetermined origin. Two separate studies have found that >75% of canine lymphomas are of B-cell origin, and 10-20% are of T-cell origin. B-cell neoplasms are associated with better response and longer remission and survival times than T-cell neoplasms. There is a strong correlation between some T-cell neoplasms and hypercalcemia (especially with T-cell lymphomas involving the thymus and bone marrow), and these tumors are associated with poorer response rates and shorter survival and remission times. Microscopical examination of lymphoid tissue is required for positive diagnosis because lymphadenopathy may be caused by non-neoplastic diseases. Examination of peripheral blood or bone marrow usually is not diagnostic except in terminal stages of the disease or in lymphocytic leukemia. Although cytology of lymph node aspirates or smears of biopsy specimens may provide a diagnosis, histopathologic examination of an involved peripheral lymph node is desirable and usually provides a definitive diagnosis. Because the submandibular nodes are often hyperplastic, they are more difficult to evaluate and should be avoided if other nodes are enlarged. Treatment: Cyclic combination chemotherapy can achieve long-term remission. Response rates to chemotherapy of 70-80% and median survival times of 10-14 mo after diagnosis may be expected; 25% may survive ≥2 yr. Most treatment regimens use a combination of cyclophosphamide, vincristine, and prednisone. The addition of asparaginase or adriamycin has improved response rates and survival times. Periodic clinical and laboratory examinations are imperative during the course of all chemotherapeutic regimens because the drugs are toxic. Adverse reactions include bone marrow suppression, increased susceptibility to infection, and hemorrhagic cystitis from
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cyclophosphamide. Use of antibiotics in an attempt to prevent these occurrences is controversial. Transfusions may be necessary. Chemotherapy is generally divided into an induction phase, in which a combination of drugs is administered intensively over a short period of time, and a maintenance phase. The following protocol has proved effective: Induction: Week 1—vincristine (0.7 mg/m2, IV), asparaginase (400 IU/kg, IP), prednisone (30 mg/m2 , PO). Week 2—cyclophosphamide (200 mg/m2, IV), prednisone (20 mg/m2, PO). Week 3—doxorubicin (30 mg/m2, IV), prednisone (10 mg/m2, PO). Week 4-6—as above for weeks 1-3, but asparaginase and prednisone are discontinued. (See Table: Weight to Body Surface Area Conversiona , for weight to body surface areas [in m2] conversion.) Maintenance: Cyclic administration of the drugs should be continued as in weeks 4-6, but the treatment interval should be extended to every 2 wk for two treatment cycles, then every 3 wk for two further treatment cycles. If relapse occurs within this time period (expected in ~50% of cases), reinduction using asparaginase and prednisone may achieve a second remission. Asparaginase is given IM or SC to reduce risk of inducing anaphylaxis. Continuous chemotherapy is then reinstituted every 2 wk, sequentially administering cyclophosphamide, vincristine, and methotrexate (0.5 mg/kg, IV) in combination with prednisone (1 mg/kg, PO, every other day). Due to delayed cardiac toxicity, the maximal cumulative dose of doxorubicin should be 150-200 mg/m2. Chlorambucil (1.4 mg/kg, PO, divided into two doses) also can be substituted for cyclophosphamide after remission is achieved. Many other protocols have been reported for the treatment of canine lymphoma; these include adriamycin as the sole agent; cytoxin, oncovin, and prednisone (COP protocol); and cytoxin, oncovin, methotrexate, and prednisone (COMP protocol). Additionally, many newer chemotherapeutic agents and immunotherapies are currently being evaluated. The diffuse alimentary form of lymphosarcoma often responds poorly to chemotherapy. However, if the lesion is localized to a segment of the intestine, surgical resection followed by chemotherapy should be performed. In this case, the prognosis is guarded to fair for long-term response. Well-differentiated lymphocytic leukemia can be treated with chlorambucil at 0.2 mg/kg, PO, for 7-10 days, followed by a reduced daily dose of 0.1 mg/kg. Remissions of 1-2 yr can be expected. Treatment of lymphoblastic leukemia has been less successful, with a median survival time of <6 mo and a complete response rate of ~30%. Disseminated intravascular coagulation (DIC) is a syndrome characterized by massive activation and consumption of coagulation proteins, fibrinolytic proteins, and platelets. It is not a primary disease, but a disorder secondary to numerous triggering events such as bacterial, viral, rickettsial, protozoal, or parasitic diseases; heat stroke; burns; neoplasia; or severe trauma. In acute, fulminant DIC, the clinical presentation is uncontrolled hemorrhaging and the inability to form a normal clot. Classically, all
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coagulation screening tests (ACT, APTT, PT, thrombin time) are prolonged, fibrin (or fibrinogen) degradation products are increased, and fibrinogen and platelet concentrations are decreased. Death is caused by extensive microthrombosis or circulatory failure, leading to single or multiple organ failure. If the animal survives the acute DIC event, a chronic form of DIC can exist. Compensatory production of coagulation proteins and platelets by the liver and bone marrow, respectively, can alter the results of coagulation screening tests such that they may be within reference ranges or even shortened, and platelet concentrations may be normal. However, DIC can usually be identified by the presence of at least three abnormal coagulation test results. Horses, even in fulminant DIC, most often have hyperfibrinogenemia because their liver can produce much fibrinogen. Treatment should be directed toward correcting the underlying problem. Supportive care is essential. Administration of balanced electrolyte solutions to maintain effective circulating volume is imperative. Administration of heparin is controversial and should be accompanied by administration of plasma to assure adequate antithrombin III activity. Congenital Thrombocytopenia Fetal and neonatal alloimmune thrombocytopenia occurs when maternal antibodies are produced against a paternal antigen on fetal platelets. A group of lambs artificially reared and fed bovine colostrum had prolonged bleeding from puncture wounds made for ear tag placement, subcutaneous bruising, weakness, and pale mucous membranes. All affected lambs died within 48 hr after birth. Thrombocytopenia was seen in whole blood, and platelets were markedly decreased on blood smears. The presence of antibodies directed against platelets was suspected because the cows from which colostrum was obtained had been used in a previous experiment in which they had been immunized against sheep blood. Caseous Lymphadenitis of Sheep and Goats This caseous abscessation of lymph nodes and internal organs caused by Corynebacterium pseudotuberculosis occurs worldwide. It is an important endemic infection in regions with large sheep and goat populations. Economic losses result from reduced weight gain, reproductive efficiency, and wool and milk production, as well as from condemnation of carcasses and devaluation of hides. Although principally an infection of sheep and goats, sporadic disease also occurs in horses and cattle (see below Corynebacterium pseudotuberculosis Infection of Horses and Cattle), and water buffalo, wild ruminants, primates, pigs, and fowl. It rarely causes regional lymphadenitis in man. Etiology and Pathogenesis: The small gram-positive rod is a facultative intracellular parasite that is found on fomites and in soil and manure contaminated with purulent exudate. Two biotypes have been identified: a nitrate-negative group that infects sheep and goats, and a nitratepositive group that infects horses. Isolates from cattle are a heterogeneous group. All strains produce an antigenically similar exotoxin with enzymatic activity (phospholipase
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D[PLD]) that appears to be leukotoxic and that can damage endothelial cells and promote spread from the initial site of infection to regional lymph nodes and visceral organs. The chemical composition of its cell wall (high lipid content) enables the organism to resist being killed by phagocytes and to maintain chronic infection. Infection may occur after C pseudotuberculosis penetrates through unbroken skin or mucous membranes; however, in most cases it probably begins when superficial skin wounds are contaminated with purulent material from ruptured abscesses from other sheep and goats. Ruptured superficial and lung abscesses are the primary sources of environmental contamination. Contaminated dipping vats and shearing, handling, and feeding equipment are responsible for spread of the organism. The pus contains large numbers of bacteria that can survive for months in hay, shavings, and soil. The disease is commonly introduced into a flock by entry of an apparently healthy carrier from an infected flock, by contact on shared pastures, or via contaminated shearing equipment. Clinical Findings: Caseous lymphadenitis is a chronic, recurring disease. A slowly enlarging, localized, and nonpainful abscess may develop either at the point of entry into the skin or in the regional lymph node (superficial or external form), from which it may spread via the blood or lymphatic system and cause abscessation of internal lymph nodes or organs (visceral or internal form). Initial infection may cause no clinical signs or may be accompanied by high fever, anorexia, anemia, and cellulitis at the infection site. Superficial abscesses enlarge and may rupture and discharge infectious pus. In sheep on range, most superficial abscesses develop in the prescapular and prefemoral region, with transmission probably occurring at shearing time. In housed goats and sheep, superficial abscesses develop mainly in the head and neck region due to transmission by contaminated feed, feeders, and other fomites. Animals with superficial abscesses show no obvious ill effects unless the location of the abscess interferes with functions such as swallowing or breathing. Abscessation may recur at the same site. Pulmonary, hepatic, and renal abscesses commonly cause “thin ewe syndrome.” Other manifestations include caseous bronchopneumonia, arthritis, abortion, CNS abscessation, scrotal abscessation, and mastitis. The visceral form is usually more extensive in sheep than in goats, with a preponderance of pulmonary involvement. The incidence steadily increases with age; clinical disease is more prevalent in adults, and up to 40% of animals in a flock can have superficial abscesses. The typical gross lesion is a discrete abscess distended by thick and often dry, greenish yellow or white, purulent exudate. In sheep, the abscess often has the classically described laminated “onion-ring” appearance in cross section, with concentric fibrous layers separated by inspissated caseous exudate. In goats, the exudate is usually soft and pasty. Diagnosis: The diagnosis can usually be based on clinical signs and flock history. For definitive diagnosis, an aspirate of an abscess should be submitted for bacteriologic examination; C pseudotuberculosis can easily be isolated, although it may be recovered in mixed
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culture with other pyogenic organisms. Suppurative lymphadenitis and abscesses can also be caused by various other pyogenic organisms, such as Actinomyces pyogenes , Staphylococcus aureus , and Pasteurella multocida . Scrotal abscesses may be confused with orchitis due to A pyogenes or with epididymitis due to Histophilus sp , Brucella ovis , or other pyogenic organisms. Emaciated animals also should be examined for ovine progressive pneumonia, caprine arthritis and encephalitis, paratuberculosis, and parasitism. Serologic testing is available commercially. Most tests detect antibodies to the PLD exotoxin. A positive test should be interpreted as exposure to the exotoxin and may indicate active infection. Severely debilitated animals may have a false negative result. Colostral titers usually disappear between 3 and 6 mo of age so that serologic testing of lambs or kids <6 mo old should be interpreted with caution. Vaccinated animals will test seropositive and should not be included in a serologic program. Treatment and Control: Treatment is usually not attempted. Although the organism is susceptible to penicillin, the formation of abscesses limits the penetration and effectiveness of antibiotics. Therefore, prophylactic and therapeutic treatment will not eliminate C pseudotuberculosis from infected flocks or individuals. Abscesses frequently recur after draining or attempted surgical excision. Prevention is based on reducing transmission of the organism from infected to susceptible animals. Emaciated animals and those with recurrent abscesses should be culled. When animals are too valuable to cull, those with developing abscesses should be isolated, and the abscesses lanced and flushed with iodine solution. Young animals should be raised in isolation from older, infected animals. However, it should be remembered that the disease can be transmitted via fomites. Older animals and those with abscesses should be shorn last, and equipment should be disinfected whenever it is contaminated with draining exudate. Skin wounds should be treated topically with iodine and sutured if necessary. Commercial vaccines reduce the incidence and prevalence of caseous lymphadenitis within a flock but neither prevent all new infections nor cure animals already infected. Currently, all contain PLD toxoid, and some also contain killed whole bacterial cells. Usually, Clostridium tetani and C perfringens type D, along with other clostridial antigens, are also included in the vaccine. An effective control program must involve vaccinating, culling, and reducing exposure to possibly contaminated fomites, such as shearing blades, dipping fluids, feeders, and feed. Vaccination should begin in lambs and kids at 3 and 4 mo of age, with annual boosters given to all breeding stock 1 mo before expected parturition. Eradication is difficult and requires rigorous culling of all infected anmals. Once the disease is at a low prevalence, vaccination should be stopped, and all seropositive, nonvaccinated animals culled. Prevention of entry of disease into a clean flock is based on serologic screening and isolation of incoming animals. Seropostive animals should not be accepted into the flock.
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Corynebacterium pseudotuberculosis Infection of Horses and Cattle In horses, C pseudotuberculosis causes ulcerative lymphangitis , an infection of the lower limbs, and chronic abscesses in the pectoral region and contagious acne. In cattle, it may cause ventral lymphadenitis, abscesses, and ulcerative dermatitis. Sporadic outbreaks have occurred in cattle in the western USA. Two to 5% of cows may be affected with large, ulcerative skin lesions and lymphangitis. Location on the animal is variable. Healing often occurs without treatment or with limited topical treatment. Abortion and mastitis may also occur. Rarely, visceral involvement has been reported. Pathogenesis and Clinical Findings: The onset of ulcerative lymphangitis is slow and usually manifests by painful inflammation, nodules, and ulcers, especially in the region of the fetlock; occasionally, the edematous swelling can extend up the entire limb. The exudate is odorless, thick, greenish white, and blood tinged. Usually, only one leg is involved. Lesions and swelling progress slowly, and the condition can become chronic with relapses. In the Southwestern USA, C pseudotuberculosis infection in horses is seasonal, with a peak incidence in late summer and fall. It results in abscessation of the lower pectoral region or ventral abdominal wall with secondary dissemination to internal organs. Clinical signs include diffuse or localized swellings, ventral pitting edema, ventral midline dermatitis, lameness, draining abscesses or tracts, fever, weight loss, and depression. Leukocytosis and neutrophilia may be present. A marked or prolonged fever indicates untoward sequelae—chronic discharge, multiple or internal abscessation, or systemic infection with abortion. Abscesses can be large, up to 20 cm in diameter before rupturing, and take months to resolve. Weight loss, colic, or ataxia may be signs of internal abscesses. Dermatitis lesions are painful and mildly pruritic with alopecia, exudation, crusting, and ulceration. The bacteria probably enter via skin wounds, arthropod vectors, and contact with fomites, such as contaminated tack and grooming equipment. Unhygienic and wet conditions predispose animals to infection, particularly of the lower legs and ventral region. However, the disease also occurs under excellent management conditions. Diagnosis: Isolation of C pseudotuberculosis from lesions is necessary for confirmation. In all forms of lymphangitis in horses, samples for culture include aspirates of abcesses, swabs of purulent exudate beneath crusts associated with folliculitis, and punch biopsies. Differential diagnoses include pyoderma, abscesses, lymphangitis (caused by Staphylococcus aureus , Rhodococcus equi , Streptococcus , or Dermatophilus ), dermatophytosis, sporotrichosis, equine cryptococcosis, North American blastomycosis, and onchocerciasis. Treatment: Lymphangitis and early abscess swellings are treated with hot packs, poultices, or hydrotherapy. Abscesses are lanced and flushed with iodine solution. Large abscesses
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require surgery. Skin lesions and grossly contaminated limbs are scrubbed daily with an iodophor shampoo. Penicillin or trimethoprim-sulfa combinations have been given; however, antimicrobial treatment may prolong the disease by delaying abscess maturation. Phenylbutazone relieves pain and swelling. General supportive and nursing care is indicated. If treatment is successful, the swelling gradually recedes over days or weeks. Severe or untreated cases often become chronic, and fibrosis and induration of the leg occurs. An experimental bacterin-toxoid was not efficacious in field trials. Cardiovascular System Introduction: Introduction The cardiovascular system comprises the heart (the pump), the veins (the vessels leading into the heart), and the arteries (the vessels leading away from the heart). The cusps of the atrioventricular valves keep blood flowing in one direction through the heart, and valvules in large veins keep blood flowing in one direction through them as well. The rate and force of contraction of the heart and the degree of constriction or dilatation of blood vessels are determined by the autonomic nervous system and hormones produced either at the heart and blood vessels (ie, paracrine or autocrine) or at a distance from the heart and blood vessels (ie, endocrine) Slightly >10% of all domestic animals examined by a veterinarian have some form of cardiovascular disease. Unlike diseases of many other organ systems, cardiovascular diseases generally do not resolve but almost always become more and more limiting and may lead to death. In addition, cardiovascular diseases may be more difficult to detect and quantify because the heart cannot be seen and is protected so well by the rib cage. Therefore, evaluation of the heart depends on heart sounds and murmurs, pressure pulses and the apex beat, the electrocardiogram, and radiology and echocardiology. Heart Rate and the Electrocardiogram: The heart beats because of a wave of depolarization that originates in the sinoatrial (SA) node at the juncture of the cranial vena cava and the right atrium. At rest, the SA node discharges ~15 times/min in the horse, >200 times/min in the cat, and 60-160 times/min in the dog. In general, the larger the species, the slower the rate of SA node discharge and the slower the heart rate. The rate of SA node discharge increases, often to nearly 300 beats/min, when norepinephrine is released from the sympathetic nerves and binds to the β1adrenoreceptors on the SA node. This cardioacceleration may be blocked by βadrenergic blocking agents (eg, propranolol, atenolol, metoprolol). The rate of SA node discharge decreases when acetylcholine released by the parasympathetic (vagus) nerves binds to the cholinergic receptors on the SA node. This vagally mediated cardiodeceleration may be blocked by a parasympatholytic (vagolytic) compound (eg, atropine, glycopyrrolate). When the SA node discharges and the wave of depolarization traverses the atria, the P wave of the electrocardiogram (ECG) is produced, and the atria contract, ejecting a
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small volume of blood into the respective ventricles. Under rare conditions, there may be atrial depolarization without contraction; this is called electromechanical dissociation. In quiet, healthy dogs, the heart rate is usually irregular. It increases during inspiration and decreases during expiration. This is termed respiratory sinus arrhythmia and results from decreased vagal activity during inspiration and increased vagal activity during expiration. Therefore, vagolytic compounds, as well as excitement, pain, or fever, usually abolish or diminish respiratory sinus arrhythmia. Heart rate is also inversely related to systemic arterial blood pressure. When blood pressure increases, heart rate decreases; when blood pressure decreases, heart rate increases. This relationship is known as the Marey reflex and occurs by the following mechanisms. When high-pressure arterial baroreceptors in the aortic and carotid sinuses detect the fall in blood pressure, they send increased afferent volleys to the medulla oblongata, which decreases vagal efferents to the SA node and causes the heart rate to increase. When blood pressure increases, heart rate slows due to increased vagal efferents to the SA node. In heart failure, the baroreceptors “believe” that blood pressure is too low, even though this may not be so. Thus, the baroreceptors initiate compensatory mechanisms (eg, arterial and arteriolar constriction, venous constriction, increase in heart rate) designed to increase blood pressure that, unfortunately, injure the heart. Once the wave of depolarization reaches the atrioventricular (AV) node in the right atrium, it travels slowly through the AV node, giving the atria time to contract and to eject the small volume of blood into the ventricles. The depolarization then travels rapidly to the subendocardium of the ventricles and to the ventricular septum. From these points, it travels slowly through the ventricular myocardium, produces the QRS complex of the ECG, and the ventricles contract. The interval on an ECG between the onset of the P wave and the onset of the QRS complex is termed the PQ or PR interval. It is a measure of the time between when the atria and ventricles were stimulated and contracted, and it is termed the AV conduction time. Whatever speeds or slows the rate of discharge of the SA node also speeds or slows conduction through the AV node. Thus, when heart rate is fast, the PQ is short; when heart rate is slow, the PQ is long. The T wave of the ECG represents repolarization of the ventricles. It is affected by electrolyte imbalance, myocardial injury, or ventricular enlargement. Repolarization of the atria is often lost in the QRS complex or appears as a “hammock” between the P wave and QRS complex. Force of Ventricular Contraction: The force with which the ventricles contract is determined by three factors: 1) the end-diastolic volume or preload, which is the volume of blood within the ventricles just before they begin to contract, 2) myocardial contractility or the inotropic state, which is the rate of cycling of the microscopic contractile units of the myocardium, and 3) the
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afterload, which is the interference to ejection of blood from the ventricle into and through the arterial tree. The afterload is measured as the peak tension the myocardium must generate to eject blood. The preload is the difference in end-diastolic pressure between the ventricle and the pleural space, divided by the stiffness of the ventricular myocardium. The end-diastolic pressure of the ventricle is determined by the ratio of blood volume and the capacity of the systemic veins to store the blood. The venous capacity depends on the degree of constriction or relaxation of the venous vascular smooth muscle. The preload is regulated predominantly by low-pressure volume receptors in the heart and large veins. When these receptors are stimulated by an increase in blood volume or by distention of the structures the receptors occupy, the body responds by making more urine and by dilating the veins—an attempt to decrease blood volume and lower the pressures in the veins responsible for venous distention. Myocardial contractility is determined by the rate of liberation of energy from ATP, which is determined, in part, by the amount of norepinephrine binding to β-1 adrenergic receptors in the myocardium. The afterload is determined by the relative stiffness of the arteries and by the degree of constriction or dilatation of the arterioles, both of which are determined by the degree of constriction or relaxation of the arterial and arteriolar vascular smooth muscle. The tone of vascular smooth muscle depends on many factors, some of which constrict the muscle (eg, α-1, angiotensin II, vasopressin, endothelin) and some of which relax the muscle (eg, β-2, atriopeptin, bradykinin, adenosine, nitric oxide). Afterload and peak tension are also determined by the preload and thickness of the ventricular wall just before ejecting. In fact, peak tension is equal to the preload times the diastolic arterial blood pressure, all divided by the end-diastolic wall thickness of the ventricle. Oxygen and the Myocardium: Oxygen is essential for the production of energy that permits all body functions (eg, muscle contraction, gland secretion, nerve conduction). The amount of oxygen available for production of this energy is termed the tissue oxygen content. The myocardial oxygen content is a balance between how much oxygen is delivered to the heart minus how much oxygen is consumed by the heart. The amount of oxygen delivered to the heart depends on how well the lung functions, how much hemoglobin (Hgb) is present to carry the oxygen, and how much blood carrying the Hgb flows through the heart muscle via the coronary arteries. Presuming the lung is functioning well and there is sufficient Hgb, the coronary blood flow will determine how much oxygen is delivered to the myocardium. The coronary blood flow is determined by the difference in pressure between the aorta (normally 100 mm Hg), from which all coronary blood originates, and the right atrium (normally 5 mm Hg), into which most coronary blood empties. Because coronary blood flows mainly during diastole when the heart is resting, and because the duration of diastole is inversely related to heart rate, then it follows that the lower the heart rate, the longer the
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period of diastole, and the greater the coronary blood flow. Optimal oxygen is delivered to the myocardium when the lung functions well, there is adequate functional Hgb, blood pressure is high, right atrial pressure is low, and heart rate is low. The amount of oxygen consumed by the heart is termed myocardial oxygen consumption. It is determined, principally, by heart rate, myocardial contractility, and afterload. Myocardial oxygen consumption is higher when each of the determinants is higher, and lower when each of the determinants is lower. Both heart rate and myocardial contractility are increased by β-l adrenergic stimulation (or by norepinephrine) and are decreased by an increase in parasympathetic stimulation; therefore, autonomic activity also influences myocardial oxygen consumption. Because afterload, or peak tension, is equal to the preload times the diastolic arterial blood pressure, all divided by end-diastolic wall thickness of the ventricle, any factor that increases preload and diastolic systemic arterial blood pressure or that decreases left ventricular end-diastolic wall thickness, increases myocardial oxygen consumption. The importance of heart rate on oxygen balance cannot be overemphasized. Increasing heart rate increases myocardial oxygen consumption and decreases the duration of ventricular diastole when coronary blood flow delivering oxygen occurs; thus increasing heart rate may result in oxygen debt and impaired cardiac performance. Oxygen is responsible for the production of the vast majority of ATP, and it is the energy transformed from ATP that fuels both contraction and, just as important, relaxation of the myocardium. Cessation of cycling and the relaxation is permitted by the energy from ATP driving calcium ions from the microscopic units of contraction into the saccules (sarcoplasmic reticulum) from which the calcium is unavailable to sustain contraction. In heart failure, inappropriate handling of calcium may be the most important factor that leads to both reduced force of contraction and reduced rate of relaxation (ie, reduced systolic as well as diastolic function). Interference to the Flow of Blood: The interference to blood flow, termed cardiac output, from either the left or right ventricle into and through the systemic arterial or pulmonary arterial trees is critical to satisfactory function of the heart and consequent perfusion of organs with adequate quantities of blood and the oxygen it contains. Most (80%) of the interference to blood flow is from the degree of constriction or dilatation of the arterioles, termed the vascular resistance; however, some interference is from the stiffness of the portion of the great arteries closest to the ventricles, termed the impedance. The ventricles eject a stroke volume into the proximal portion of the great arteries, which expand to accommodate the stroke volume; when the ventricles are relaxed, the distended great arteries constrict and keep blood moving through the arterioles into the capillaries and veins. Of course, none of the stroke volume returns to the ventricle that ejected it because the semilunar valves close and prevent such regurgitation.

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One of the most important features of heart failure that leads to morbidity is increased resistance of arterial, arteriolar, and venous smooth muscle. This results because of increased angiotensin II and vasopressin due to (incorrect) compensatory feedback from the high-pressure baroreceptors to the medulla that blood pressure is too low. If the left ventricle is unable to eject a normal stroke volume or cardiac output, it is reasonable that the ventricular function might be improved by decreasing both vascular resistance and impedance—which is precisely why drugs that relax vascular smooth muscle are useful. Principles Of Therapy: Overview See also systemic pharmacotherapeutics of the cardiovascular system, Systemic Pharmacotherapeutics Of The Cardiovascular System: Introduction. The following are general goals of therapy for heart disease. 1) Chronic stretch on myocardial fibers should be minimized because chronic stretch injures and irritates fibers, causes them to consume excess quantities of oxygen, and leads to their death and replacement by fibrous connective tissue (remodeling). 2) Edema fluid should be removed because it makes the lung wet, heavy, and stiff, and causes ventilationperfusion inequalities and fatigues muscles of ventilation. 3) The circulation should be improved and the amount of regurgitation (most often mitral regurgitation) decreased. Improved circulation enhances blood flow to important organs, and reducing mitral regurgitation decreases stretch on the left atrium and pulmonary veins, decreases pulmonary capillary pressure, and decreases edema formation. 4) Heart rate and rhythm should be regulated. A heart beating too slowly fails to eject enough blood. A heart beating too rapidly does not have time and consumes too much oxygen at a time when there is too little coronary blood flow. A heart beating too irregularly may deteriorate into ventricular fibrillation and sudden death. 5) Oxygenation of the blood should be improved. Inadequate oxygenation leads to inadequate energy to fuel both contraction and relaxation of the myocardium. Inadequate oxygenation of the myocardium may also lead to arrhythmia. 6) β1-adrenergic receptors should be “up regulated.” “Down regulation” of β1-adrenergic receptors interferes with the ability to fight diseases of other organ systems. 7) The likelihood of thromboembolism should be minimized. Cats with hypertrophic cardiomyopathy may shed emboli from the enlarged left atrium, which may plug up major arterial branches and lead to ischemia and death. 8) Mature heartworms and microfilariae should be killed. Mature heartworms may initiate severe changes in the pulmonary arteries that ultimately impede blood flow through the lung. The ultimate goals of therapy for cardiovascular disease are achieved when the animal can be classified as functional Class I, the respiratory and heart rates are not increased at rest, and there is a respiratory sinus arrhythmia. Common Therapeutic Agents

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Furosemide is a diuretic that decreases resorption of provisional urine at the loop of Henle. It is also a venodilator when used IV. Theophylline is a bronchodilator and strengthens the muscles of ventilation. Chlorothiazide is a diuretic that decreases resorption of provisional urine at the distal convoluted tubule. It is used when furosemide diuresis either stops or is inadequate. (Note: All thiazides possess similar actions.) Spironolactone is a potassium-sparing diuretic that blocks aldosterone; it exerts its diuretic effect at the distal convoluted tubule. Amiloride and triamterine have similar modes of action. Digitalis glycosides exert their effects by inhibiting membrane Na-K-ATPase. Digoxin increases the force of myocardial contraction, slows the heart rate, and improves baroreceptor function. It also strengthens muscles of ventilation. Enalapril is an angiotensin-converting enzyme inhibitor that blocks the conversion of angiotensin I to angiotensin II. It reduces afterload, thereby improving cardiac output and reducing mitral regurgitation. It also improves baroreceptor function and is a venodilator. Procainamide is an antiarrhythmic compound used to suppress ventricular arrhythmias. It is used most often for ventricular arrhythmias that are not lifethreatening; it is given most often orally. Quinidine is similar to procainamide but is the drug of choice for treating atrial fibrillation in horses. Lidocaine is used only IV for emergency ventricular arrhythmias. Mexilitine is an oral compound similar to lidocaine. Atenolol, propranolol, and metoprolol are β-andrenergic blockers that slow the heart rate, suppress arrhythmias, and “up regulate” adrenergic receptors. Diltiazem is a calcium-channel blocker that is useful for slow ventricular rate in animals with atrial fibrillation. It is also used to decrease myocardial stiffness in cats with hypertrophic cardiomyopathy. Verapamil is also a calcium-channel blocker, but it reduces myocardial contractility more than diltiazem. Sotolol and amiodorone are antiarrhythmic compounds useful for managing all forms of arrhythmias, but there is relatively little clinical experience with them. Atropine and glycopyrrolate block the effects of the vagus nerve on the SA node. Because the vagus nerve slows discharge of the SA node and heart rate, these compounds speed heart rate and may be useful when the heart beats too slowly. Nitroglycerine is a venodilator that is usually applied in a paste form to the skin inside of the earflap or thigh. By dilating peripheral veins, blood pools in those veins, and left ventricular preload and pulmonary edema are decreased. Aspirin and coumadin are anticoagulants that may prevent thromboembolism in cats with cardiomyopathy. Taurine and l-carnitine are amino acids useful in preventing dilated cardiomyopathy in cats (taurine) and, in a limited number of dogs (l-carnitine). Thiacetarsamide is used to kill mature heartworms. Ivermectin and milbemycin are used to kill microfilariae. Anomalies Of Derivatives Of The Aortic Arches: Overview Embryonic aortic arches give rise to the carotid arteries (third pair of arches), the arch of the aorta (left fourth arch), and the pulmonary arteries and ductus arteriosus

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(sixth pair of arches). The remainder of the arches become vestigial. Congenital defects may arise if development or dissolution of the aortic arches is disrupted. Patent Ductus Arteriosus In fetal life, oxygenated blood within the main pulmonary artery is shunted into the descending aorta through the ductus arteriosus, thereby bypassing the nonfunctional lungs. At birth, several factors mediate closure of the ductus, which effects separation of the systemic and pulmonary circulatory systems. Inflation of the lungs allows the pulmonary circulation to function as a low pressure system, and closure of the ductus prevents shunting of blood from the high pressure systemic circulatory system into the pulmonary artery. Pathophysiology: Persistence or patency of the ductus with an otherwise normal systemic and pulmonary circulatory system results in significant shunting of blood from left to right, ie, systemic to pulmonary. Because the pressure within the aorta is always higher than that of the pulmonary artery, shunting is continuous and produces the classic continuous, machinery-like murmur. The result is a volume overload of the pulmonary arteries and veins, left atrium, and left ventricle. Dilatation of these structures becomes evident. Left atrial and left ventricular dilatation may result in cardiac arrhythmias. Chronic volume overloading and dilatation of the left-sided cardiac chambers usually result in signs of left-sided congestive heart failure (pulmonary edema, cough, fatigue). Therefore, most untreated cases develop refractory congestive heart failure. Animals with a small ductus may reach adulthood without signs of heart failure but are at an increased risk of endocarditis. In a few untreated cases, increased pulmonary blood flow induces pulmonary vasoconstriction and development of pulmonary hypertension, which has several important implications. Shunting through the ductus slows and reverses, which causes disappearance of the murmur and occurrence of caudal cyanosis; the right ventricle becomes dilated and hypertrophied as a result of pulmonary vasoconstriction; and perfusion of the kidneys with desaturated blood causes excessive release of erythropoietin and subsequent polycythemia. Thus, if the ductus is shunting right to left, clinical signs of right ventricular failure (ascites, fatigue) and polycythemia (exercise intolerance, seizures) will predominate. In some cases, a right-to-left shunt is present at birth secondary to a patent ductus and retention of pulmonary vasculature (congenital pulmonary hypertension). Clinical Findings and Treatment: In animals with a PDA that shunts from left to right, a prominent, continuous, machinery-like murmur is present. The systolic component is loudest, heard best over the aortic valve area, and often associated with a precordial thrill. The diastolic component is softer and heard best over the pulmonic valve area, occasionally best at the axillary area (in some cases, the ductus remains open for several days after birth; therefore, a continuous murmur may be detected during examination of the neonate). Femoral pulses are bounding. Most young animals do not demonstrate clinical signs.
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Those with a large shunt and older animals often have signs of left-sided congestive heart failure, eg, cough, tachypnea, exercise intolerance, and weight loss. Consistent electrocardiographic features include evidence of left ventricular and left atrial enlargement. A spectrum of cardiac arrhythmias may be seen, including both atrial and ventricular premature complexes. Radiography demonstrates left atrial and left ventricular enlargement, prominent pulmonary vessels, aortic and pulmonic aneurysmal dilatations, and variable degrees of pulmonary edema. Echocardiography is not crucial in the diagnosis of PDA but is valuable in ruling out concurrent congenital cardiac defects. Surgical ligation of the ductus is curative and indicated in all cases deemed satisfactory anesthetic risks, considering the risk of congestive heart failure and endocarditis in untreated cases. If present, congestive heart failure should be medically managed (with diuretics, vasodilators, etc) before anesthesia and surgery. In animals with a PDA that shunts from right to left, there is usually a history of lethargy, exercise intolerance, and collapse. Careful examination may reveal differential cyanosis. The second heart sound may be split, and there may be a soft diastolic murmur of pulmonic insufficiency. A continuous murmur is not present and pulses are not bounding. The finding of polycythemia in a young animal with the above clinical signs should prompt further cardiac diagnostics. Electrocardiography demonstrates severe right ventricular enlargement and occasional arrhythmias. Radiographically, there is enlargement of the right ventricle and usually aortic and pulmonic aneurysmal dilatations. Echocardiography is indicated in these cases and will demonstrate right ventricular dilatation and hypertrophy. The right ventricular outflow tract is enlarged. Contrast echocardiography can be used to confirm the diagnosis. After the injection of agitated saline into a peripheral vein, microbubbles will be seen within the abdominal aorta but not within the heart. Ligation of the ductus is contraindicated because this forces all right ventricular output through the constricted pulmonary arteries and leads to right ventricular failure. Therapy in these cases involves control of polycythemia through periodic phlebotomies. Long-term prognosis is poor. Persistent Right Aortic Arch In this vascular ring anomaly, the right aortic arch persists, which causes obstruction of the esophagus at the level of the heart base. The esophagus is encircled by the persistent arch on the right, by the ligamentum arteriosum to the left and dorsally, and by the base of the heart ventrally. Persistent right aortic arch (PRAA) has been reported in cattle, horses, cats, and dogs. Breed predilections exist for German Shepherd Dogs and Irish Setters. For clinical signs and treatment, see dilatation of the esophagus , Dilatation of the Esophagus. Other vascular ring anomalies have been reported and result in similar findings to PRAA. These congenital defects do not cause clinical signs referable to the cardiovascular system—signs of regurgitation and aspiration pneumonia predominate.
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Aortic Stenosis Left ventricular emptying may be obstructed at three locations: 1) subvalvular, consisting of a fibrous ridge of tissue within the left ventricular outflow tract; 2) valvular; and 3) supravalvular or obstruction distal to the aortic valve. The most common form in the dog is subaortic stenosis. Breed predilections have been identified for Boxers, Golden Retrievers, and Newfoundlands. Pathophysiology: Aortic stenosis induces left ventricular hypertrophy, the degree of which depends on the severity of the stenosis. In severe cases, left ventricular output may be decreased, especially during exercise. The major ramification of left ventricular hypertrophy is the creation of areas of myocardium with poor perfusion. Myocardial ischemia is a major factor in the development of serious life-threatening ventricular arrhythmias. Clinical Findings and Treatment: Clinical signs do not consistently parallel the severity of stenosis. There may be a history of syncope and exercise intolerance. Animals with no history of illness may die suddenly, and the defect is first detected at necropsy. An ejection-type systolic murmur heard best at the aortic valve area is present. The intensity of the murmur correlates fairly well with the degree of stenosis, and may increase as animals mature, reflecting progressive stenosis. Puppies without detectable murmurs should not be considered free of disease until they reach 6 mo of age because the murmur may be very soft in the first months of life. In moderate to severe cases, femoral pulse strength is diminished. Electrocardiography may reveal evidence of left ventricular enlargement and ventricular premature complexes. Holter monitoring should be used in syncopal animals to define the underlying arrhythmia. Radiographically, there is variable left ventricular enlargement and poststenotic dilatation of the aorta. Echocardiography, including Doppler evaluation, is recommended. The degree of left ventricular hypertrophy and ejection velocity through the defect allow determination of severity and need for intervention. Treatment options include balloon valvuloplasty and surgical resection. The use of βadrenergic blockers (propranolol, atenolol) have been advocated in animals experiencing syncope to reduce the frequency of arrhythmias. Affected animals should not be used for breeding. Pulmonic Stenosis Pulmonic stenosis is a common congenital cardiac defect in dogs. It results in obstruction to right ventricular emptying due, in most cases, to partial fusion and dysplasia of the pulmonic valve cusps. Pathophysiology: The right ventricle must generate increased pressure during systole to overcome the stenosis, which often leads to dramatic right ventricular hypertrophy. As the right ventricle hypertrophies, its compliance diminishes, which leads to increased
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right atrial pressures and venous congestion. The jet of blood passing through the stenosis deforms the wall of the main pulmonary artery and results in a poststenotic dilatation. In severe cases, right-sided congestive failure is present. Clinical Findings and Treatment: Affected animals may have a history of failure to thrive and exercise intolerance. Right-sided congestive heart failure may be present and is characterized by ascites or peripheral edema. A prominent ejection-type systolic murmur is present and heard best at the pulmonic valve area. A corresponding precordial thrill is usually present. Jugular distention and pulsations may also be present. Electrocardiography will demonstrate evidence of right ventricular enlargement in most cases. Radiographic abnormalities include right ventricular enlargement, an aneurysmal dilation of the main pulmonary artery, and diminished pulmonary vasculature. Echocardiography is indicated in these cases and demonstrates right ventricular dilatation and hypertrophy, interventricular septal flattening, and thickened and relatively immobile pulmonic valve cusps. Doppler evaluation is valuable in determining the severity of the stenosis. Based on severity, which is reported as the pressure gradient across the valve, the need for intervention can be assessed. Animals with moderate or severe pulmonic stenosis will benefit from balloon valvuloplasty or surgical resection. Palliative therapy with diuretics and vasodilators should be initiated if right-sided congestive heart failure is present. Atrial Septal Defects A communication between the atria may be the result of a patent foramen ovale or a true atrial septal defect. During fetal life, the foramen ovale, a flapped oval opening of the interatrial septum, allows shunting of blood from the right atrium to the left atrium, in order to bypass the nonfunctional lungs. At birth, the drop in right atrial pressure causes the foramen ovale to close and shunting to cease. Increased right atrial pressure may reopen the foramen ovale and allow shunting to resume. A true atrial septal defect is a consistent opening of the interatrial septum, which allows blood to shunt from the atrium with the greater pressure. Septum secundum defects occur high in the interatrial septum, near the foramen ovale, and are the most common type. Septum primum defects are located lower in the interatrial septum, near the atrioventricular junction. Ventricular Septal Defects Ventricular septal defects are most commonly located in the membranous portion (subaortal) of the septum, near the level of the atrioventricular valves. They vary in size and hemodynamic significance. Defects of the muscular septum may also occur. Ventricular septal defects may occur with other congenital cardiac anomalies. This defect is heritable in miniature swine. Tetralogy of Fallot
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Tetralogy of Fallot is the most common defect that produces cyanosis. It results from a combination of pulmonic stenosis, high ventricular septal defect, right ventricular hypertrophy, and varying degrees of dextroposition and overriding of the aorta. The right ventricular hypertrophy is secondary to the obstruction to right ventricular outflow. The pulmonic stenosis component may be valvular or infundibular, or both. Canine breeds predisposed to tetralogy of Fallot include the Keeshond, English Bulldog, miniature Poodle, miniature Schnauzer, and Wirehaired Fox Terrier. A polygenic trait has been found in the Keeshond. This defect has been recognized in other breeds of dogs and in cats. Pathophysiology: The hemodynamic consequences of tetralogy of Fallot depend primarily on the severity of the pulmonic stenosis and on the size of the ventricular septal defect. The direction and magnitude of the shunt through the septal defect depends on the degree of right ventricular obstruction. If the pulmonic stenosis is mild and right ventricular pressures are only modestly increased, blood will shunt primarily from left to right. When pulmonic stenosis is severe, the increased right ventricular pressures will result in shunting from right to left. Consequences include reduced pulmonary blood flow (resulting in fatigue, shortness of breath) and generalized cyanosis (resulting in polycythemia, weakness). Due to shunting of venous blood into the aorta and consequent hypoxia, the kidneys are stimulated to release erythropoietin, which results in polycythemia ( Polycythemia: Introduction). The increased blood viscosity associated with polycythemia can have significant hemodynamic effects, such as sludging of blood and poor capillary perfusion. Animals with severe polycythemia often have a history of seizures. Clinical Findings and Treatment: Typical historical features include stunted growth, exercise intolerance, cyanosis, collapse, and seizures. A precordial thrill may be felt in the area of the pulmonic valve, and in most cases, a murmur of pulmonic stenosis is present. The intensity of the murmur is attenuated when severe polycythemia is present. Electrocardiographically, a pattern of right ventricular enlargement is usually seen, and arrhythmias are infrequent. Radiographs demonstrate variable right heart enlargement. Pulmonary vessels are undersized, often including the main pulmonary artery. Echocardiography will confirm the diagnosis. Overriding (rightward displacement) of the aortic root, right ventricular hypertrophy, and a ventricular septal defect are evident. The left-sided chambers may be small. Routine contrast echocardiography will demonstrate shunting from right to left at the level of the septal defect. Flow through the defect can also be detected by Doppler echocardiography. β-Adrenergic blockade has been used to reduce the dynamic component of right ventricular outflow obstruction and to attenuate β-adrenergic-mediated decreases in systemic vascular resistance. Increases in systemic vascular resistance will lower the magnitude of shunting. Polycythemia should be controlled by periodic phlebotomy. When the PCV exceeds 68, intervention is indicated. Up to 20 mL/kg of blood can be
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removed and replaced with a crystalloid solution (eg, lactated Ringer's or saline). The prognosis is guarded, but animals with mild to moderate shunting may reach adulthood. Surgical correction of tetralogy of Fallot is rarely performed due to the attendant mortality and expense. Palliative surgical options include anastomosis techniques to increase pulmonary blood flow. These procedures are generally effective in reducing signs of pulmonary hypoperfusion and systemic hypoxia. In some cases, reducing pulmonic stenosis is palliative. Surgical valvuloplasty or balloon valvuloplasty are options. Mitral Valve Dysplasia Congenital malformation of the mitral valve complex (mitral valve dysplasia) is a common congenital cardiac defect in the cat. Canine breeds predisposed are Bull Terriers, German Shepherd Dogs, and Great Danes. Mitral valve dysplasia results in mitral insufficiency and systolic regurgitation of blood into the left atrium. Any component of the mitral valve complex (valve leaflets, chordae tendineae, papillary muscles) may be malformed. Often, more than one component is defective. Pathophysiology: Malformation of the mitral valve complex results in significant valvular insufficiency. Chronic mitral regurgitation leads to volume overload of the left heart, which results in dilatation of the left ventricle and atrium. When mitral regurgitation is severe, cardiac output decreases, which results in signs of cardiac failure. Dilatation of the left-sided chambers predisposes affected animals to arrhythmias. In some cases, malformation of the mitral valve complex causes a degree of valvular stenosis as well as insufficiency. Clinical Findings and Treatment: Clinical signs correlate with the severity of the defect. Affected animals usually display signs of left-sided heart failure, including weakness, cough, and exercise intolerance. A holosystolic murmur of mitral regurgitation is prominent at the left cardiac apex. A diastolic heart sound (gallop rhythm) is present in some cases. Affected animals may have a precordial thrill over the left cardiac apex. Atrial arrhythmias (atrial premature complexes, atrial fibrillation) are common. There may also be evidence of both left atrial (widened P waves) and left ventricular enlargement. Thoracic radiographs reveal severe left atrial enlargement. Left ventricular enlargement is also present, and pulmonary veins are congested. Echocardiography demonstrates malformation of the mitral valve complex (fused chordae tendineae and thickened, immobile valve leaflets) and left atrial and ventricular dilatation. Doppler echocardiography demonstrates severe mitral regurgitation. If present, mitral stenosis can be identified. Prognosis for animals with clinical signs is poor. Mildly affected animals may remain free of clinical signs for several years. See Therapy of Congestive Heart Failure for therapy of progressive left-sided heart failure. Tricuspid Dysplasia
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Congenital malformation of the tricuspid valve complex is seen occasionally in dogs. Breeds predisposed are Labrador Retrievers and German Shepherd Dogs. Tricuspid dysplasia results in tricuspid insufficiency and systolic regurgitation of blood into the right atrium . In Ebstein's anomaly, a recognized variant of tricuspid dysplasia, the tricuspid valve is displaced toward the cardiac apex. Pathophysiology: Malformation of the tricuspid valve results in significant valvular insufficiency. Chronic tricuspid regurgitation leads to volume overload of the right heart, which results in dilation of the right ventricle and atrium. Pulmonary blood flow may be decreased and result in fatigue and tachypnea. As the pressure in the right atrium increases, venous return is impaired, which results in ascites. Clinical Findings and Treatment: Clinical signs correlate with the severity of the defect. Affected animals usually display signs of right-sided heart failure, including jugular distention and pulsation, edema, ascites, tachypnea, and exercise intolerance. A harsh holosystolic murmur of tricuspid regurgitation is prominent at the right cardiac apex. Atrial arrhythmias, especially paroxysmal atrial tachycardia, are common and become serious enough to cause death. Thoracic radiographs reveal severe right atrial and right ventricular enlargement. The caudal vena cava may be significantly enlarged. Echocardiography demonstrates malformation of the tricuspid valve and usually severe right atrial and ventricular dilatation. Doppler echocardiography demonstrates severe tricuspid regurgitation. Prognosis for animals with clinical signs is guarded. Periodic abdominocentesis may be needed to control peritoneal effusions. Diuretics, vasodilators, and digoxin may also be indicated. Ectopic Heart Ectopic heart is most common in cattle, in which the heart is located outside the thoracic cavity, usually in the ventral cervical area. Displacement through a defective sternum or through ribs usually results in neonatal death, although long-term survival is possible with other types of displacement. Cardiac Insufficiency And Failure: Overview Heart disease must be distinguished from heart failure. Heart disease refers to a condition in which there is an abnormality of the heart, whereas heart failure exists when the heart is unable to meet the circulatory demands of the body. Most often, the development of clinical signs such as cough, edema, and tachypnea indicate the presence of heart failure. Signs of heart failure may be more pronounced in active animals because their circulatory demands are higher; likewise, signs of heart failure may be delayed in sedentary animals because their cardiovascular systems are rarely challenged. In general, heart failure may occur secondary to decreases in stroke volume or to abnormal heart rates.
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Decreases in Stroke Volume: Stroke volume (the amount of blood ejected each cycle from either ventricle) may decrease secondary to reductions in preload, impaired contractility, increased afterload, or inadequate valvular function. A significant reduction in preload (analogous to venous return) may result in a decreased stroke volume and consequent heart failure. Examples include shock secondary to hypovolemia or hemorrhage, excessive use of diuretics, pericardial effusion with tamponade, and hypertrophic cardiomyopathy. Impaired contractility decreases stroke volume and can precipitate congestive heart failure; this occurs in dilated cardiomyopathy of large-breed dogs and in cardiomyopathy of overload (myocardial failure secondary to unligated PDA or chronic valvular disease). When there is an increased afterload, a greater than usual deterrent to ventricular emptying exists, which may result in partial ventricular emptying and a decreased stroke volume; this occurs in severe hypertension (pulmonary or systemic) and in aortic or pulmonic stenosis. The AV valves (mitral and tricuspid valves) normally prevent blood from rushing back into the atria during ventricular contraction. When valve function is inadequate or insufficient, blood reenters the atria causing atrial dilation, reducing the amount of forward flow, and consequently decreasing stroke volume. The most common causes of valvular insufficiency are degenerative valve disease (endocardiosis) and infective endocarditis. The pathologic changes can be predicted—when there is insufficiency of the tricuspid valve due to infective endocarditis, tricuspid valvular insufficiency would be expected, as well as right atrial enlargement, vena caval congestion, and ascites. Abnormal Heart Rates: An abnormally slow rate (bradycardia) may result in decreased cardiac output. Animals with bradycardia (sick sinus syndrome, third-degree AV block) often experience syncope as a result of decreased cerebral perfusion, which may occur when cardiac output drops. An abnormally fast rate (tachycardia) may also result in decreased cardiac output because there is insufficient time for ventricular filling. Animals with tachycardia (rapid atrial fibrillation, ventricular tachycardia) usually have reduced cardiac output, clinical signs of weakness, and often syncope. Left-sided Congestive Heart Failure: Left atrial pressure rises whenever left ventricular emptying is encumbered or mitral insufficiency exists. Pulmonary venous flow is impeded and pulmonary venous pressure is increased, which ultimately leads to the formation of pulmonary edema. Cough, which is a consistent feature of left-sided CHF, typically follows activity or is nocturnal. It is initially caused by edema-induced distortion of the pulmonary interstitium. As pulmonary edema worsens, fluid enters the alveoli and airways, causing the cough to increase in intensity and frequency, and rales are present on auscultation. Other signs of pulmonary edema secondary to left-sided CHF include tachypnea, orthopnea (labored breathing while recumbent), and dyspnea. Other clinical signs of left-sided CHF include exercise intolerance, tachycardia, and occasionally weight loss. Due to the dramatic
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impact of pulmonary edema, the development of left-sided congestive heart failure is almost always apparent. Right-sided Congestive Heart Failure: An increased in right atrial pressure impedes venous flow from the cranial and caudal vena cava, resulting in systemic venous congestion. Clinically, this is manifested as jugular venous distention, subcutaneous edema, and ascites. The pattern of subcutaneous edema is fairly species-specific—it is uncommon in dogs, generally involves the submandibular and brisket area in cattle, and is seen in the preputial and mammary area in horses. Cats rarely have subcutaneous edema but often develop pleural effusion (hydrothorax). Systemic congestion also causes enlargement of the liver and spleen and may result in pericardial effusion ( Pericardial Effusion). The presence of fluid within the pericardial sac muffles heart sounds. Ascites is detected by abdominal ballotment. Fluid from the pericardial sac, peritoneal cavity, and pleural space should be analyzed; it is usually a modified transudate. Pericardial effusion and subcutaneous edema are both associated with low-amplitude ECG waveforms. Generalized Congestive Heart Failure: Diseases affecting one side of the heart often precipitate failure of the other side and cause signs of both left- and right-sided CHF. As congestion worsens, left-sided signs predominate due to the severe consequences of pulmonary edema. Diet: A sodium-restricted diet is recommended and is most easily accomplished by feeding a prescription-type pet food. Recipes are also available for those who prefer to formulate diets at home. A list of sodium-free snacks is also helpful for owners. In large animals, access to salt blocks should be prevented. Diuretics: Diuretics are the mainstay therapy in the management of animals with pulmonary edema. Of the several types of diuretics available (loop diuretics, thiazides, potassiumsparing), the loop diuretics (eg, furosemide) are most commonly used. Furosemide is a potent diuretic that inhibits the resorption of sodium, potassium, chloride, and hydrogen ion from the ascending limb of the loop of Henle—as these ions are excreted, water follows. The dose and frequency of furosemide required depends on the severity of pulmonary edema and the degree of respiratory distress. In severe, life-threatening cases, furosemide should be administered IV at relatively high dosages, ie, 4-6 mg/kg. When administered IV, the onset of action of furosemide is 5 min, and its effects peak at 30 min and wane at 2 hr. Once animals with CHF have been stabilized, furosemide is usually continued orally at maintenance dosages of 0.5-1.0 mg/kg, s.i.d. or b.i.d. In managing chronic cases, furosemide should be administered at the lowest dose that will control pulmonary edema and its attendant clinical signs, including cough and respiratory distress. Side effects of furosemide may include volume depletion and prerenal azotemia, hypokalemia, and metabolic alkalosis (via renal loss of hydrogen). Vasodilators:
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Vasoconstriction is an important compensatory mechanism that occurs when cardiac output is compromised. Although beneficial in short-term situations, sustained vasoconstriction in chronic heart disease actually hastens the development of clinical signs and cardiac failure. Use of vasodilators (angiotensin-converting enzyme [ACE] inhibitors) to block excessive vasoconstriction results in significant increases in quality of life and survival times. ACE inhibitors are indicated in the treatment of mild to severe left-sided CHF in the dog. By reducing vasoconstriction and excessive systemic vascular resistance, ACE inhibitors improve cardiac output and reduce regurgitant fraction when mitral insufficiency is present. The use of vasodilators (eg, enalapril) has become an important part of treatment strategy in animals with heart disease. In a recent multicenter study involving 211 dogs with congestive heart failure, the addition of enalapril to conventional therapy resulted in an improvement in heart failure scores and a decrease in heart rate, frequency of cough, and degree of pulmonary edema. Side effects occurred with equal frequency in the placebo-treated group, the most common being anorexia, vomiting, and azotemia. Hypotension is rare and typically occurs when aggressive therapy with ACE inhibitors is begun in a volume-depleted animal. Clinically, the most significant concern is the development of azotemia secondary to reduced renal perfusion. Although the risk is low, it is recommended that renal function be determined before ACE inhibitor therapy is started. It is also advisable to decrease the dosage of the diuretic by ~25% and to measure levels of the BUN and creatinine 5-7 days after starting ACE inhibitor therapy. If azotemia develops or worsens, the dosage of the diuretic should be decreased. If azotemia persists despite diuretic dose adjustment, the frequency of enalapril administration should be decreased to once daily. It is prudent to monitor renal function (BUN and creatinine) periodically in older animals receiving enalapril and a diuretic. Enalapril should be initiated at 0.5 mg/kg, s.i.d.; if the response to treatment is inadequate, the dosage may be increased to 0.5 mg/kg, b.i.d. Enalapril is approved in the USA for use in dogs. Other ACE inhibitors used (but not approved) include captopril (0.5-1.0 mg/kg, t.i.d.) and benazepril (0.25 mg/kg, s.i.d.). Unlike enalapril and captopril, benazepril is excreted by the liver and may be useful in animals with heart failure and renal insufficiency. Although enalapril and captopril are most commonly used, there are other vasodilators available. Hydralazine directly dilates arterioles presumably by increasing vasodilatory prostaglandins (PGI2). It is specific for arteriolar vasodilation and has little effect on venous tone. Hydralazine decreases pulmonary capillary wedge pressure (similar to left atrial pressure) and increases cardiac index. Hypotension and tachycardia are common side effects, and it is recommended that animals be hospitalized and carefully monitored (blood pressure, electrocardiography) when instituting therapy. Considering the potential for serious side effects of hydralazine and the safety and efficacy of ACE inhibitors, it is not surprising that the use of hydralazine has significantly declined. However, the cost is significantly lower than that of ACE inhibitors, and it may be considered when there are strict financial limitations. The
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initial dosage is 1 mg/kg, PO, to be increased in increments of 1 mg/kg, up to 3 mg/kg depending on therapeutic response. The effective dose is then administered twice daily. If hypotension occurs, hydralazine should be discontinued for 24 hr and then resumed at one-half the previous dosage. Persistent tachycardia should also prompt a reduction in the dosage; occasionally, digoxin or a β-adrenergic blocker are required to control heart rate. In a significant proportion of cases, recurrent vomiting and diarrhea necessitate discontinuation of this drug. Nitroglycerin is a useful venodilator in cases of acute pulmonary edema. By increasing venous capacitance, preload is decreased and blood volume is essentially shifted from the thorax to the abdomen. One major advantage is that because nitroglycerin can be applied to the skin (it is transcutaneously absorbed), administration is not stressful to the animal. The dose of 2% nitroglycerin ointment is 0.3-0.6 cm/kg, applied every 4-6 hr. Gloves should be worn by the person applying the ointment, and care should be taken to avoid contact with the ointment once it has been applied. The previous dose should be removed before applying subsequent doses of the ointment. Side effects are infrequent, but excessive use may result in hypotension, lethargy, and vomiting. Tolerance may occur with chronic use; therefore, nitroglycerin-free periods should be planned every day or two. Sodium nitroprusside can also be used in acute congestive heart failure because it causes rapid vasodilation. Unlike nitroglycerin, sodium nitroprusside is a balanced vasodilator, causing dilatation of both arterioles and veins. The result is a decrease in both systemic vascular resistance and preload and an increase in cardiac output. Because the half-life is very short, sodium nitroprusside must be administered as a constant rate infusion. In addition, its potential to cause systemic hypotension warrants careful blood pressure monitoring during the infusion. It is commonly administered in conjunction with an infusion of dobutamine, a positive inotropic agent (see below). Dobutamine further increases cardiac output and mitigates the hypotensive effects of sodium nitroprusside. The initial infusion rate of nitroprusside should be 1 µg/kg/min, with increases in increments of 1 µg/kg/min every 5 min until the mean arterial pressure is ~70 mm Hg. It is uncommon to exceed 5-7 µg/kg/min. If systemic hypotension occurs, the infusion should immediately be stopped. Due to the short half-life, blood pressure will increase once the infusion has been stopped, and the infusion can be restarted at a lower rate. Positive Inotropic Agents: These agents increase cardiac contractility and are indicated when myocardial function, specifically contractility, is impaired. Dilated cardiomyopathy and chronic, advanced degenerative valve disease are two common indications in small animals. The digitalis glycosides are the most often used positive inotropic agents. Digoxin and digitoxin increase the intracellular concentration of calcium causing a modest increase in cardiac contractility. Digoxin is the most commonly used digitalis glycoside; it is available in tablet, elixir, and IV forms. When administered orally in dogs, 4-5 days of treatment are required to achieve stable blood levels; therefore, oral digitalization is
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ineffective in acute myocardial failure. The dosage of digoxin in dogs is 0.005-0.010 mg/kg, PO, b.i.d. For large-breed dogs, dosing digoxin at 0.22 mg/m2 is recommended to reduce the frequency of side effects. (See Table: Weight to Body Surface Area Conversiona , for weight to body surface area [in m2] conversion.) Rapid digitalization results in toxicity and is not recommended. Digoxin is renally excreted and therefore should be used with caution in animals with renal insufficiency, if at all. In these animals, digitoxin is the preferred digitalis glycoside because it is metabolized by the liver. Side effects of digitalis are common because the therapeutic index is narrow. Common side effects include depression, anorexia, vomiting, diarrhea, and cardiac arrhythmias. Serious toxicity can usually be avoided by following these guidelines: 1) Renal function should be determined before beginning digitalis therapy; if renal insufficiency is present, the dosage should be decreased or digitoxin used. 2) The animal's diet should not be changed dramatically when starting digitalis; dietary changes may interfere with appetite, which is monitored as an indicator of toxicity. 3) Client communication is essential—owners should be instructed to call if any signs of toxicity develop. The drug should be temporarily discontinued or the dose reduced when side effects are first noted to prevent more serious side effects from occurring. It is advisable to obtain a serum digitalis level after 2 wk of therapy to ensure that the drug is being dosed appropriately. A serum sample should be obtained 8 hr after the last dose has been administered. For most laboratories, the normal range is 1.0-2.5 ng/mL. The dose should be altered accordingly if the level is outside the reference range. Electrolyte abnormalities, particularly hypokalemia, increase the risk of digitalis toxicity. Dobutamine is a synthetic catecholamine that primarily stimulates β1-adrenergic receptors. Through stimulation of these receptors, dobutamine mediates an increase in cardiac contractility. Its positive inotropic effects are much greater than those of the digitalis glycosides. Dobutamine must be administered as a constant rate infusion, preferably by an infusion pump. Dobutamine is diluted with 5% dextrose and administered at 5-15 µg/kg/min. The major indication in veterinary medicine is severe myocardial failure secondary to dilated cardiomyopathy, although it may be used in dogs with degenerative valve disease and concurrent myocardial failure. Dobutamine can cause cardiac arrhythmias—therefore, ECG monitoring is critical during the infusion. If cardiac arrhythmias worsen during the infusion, the rate of administration should be decreased or the infusion stopped. Dobutamine also increases conduction of the AV node; therefore, if atrial fibrillation is present, the ventricular response may increase excessively. For this reason, it is recommended that dogs with atrial fibrillation be adequately digitalized before receiving a dobutamine infusion. Although plasma dobutamine levels decrease rapidly 3 min after the infusion, beneficial effects often persist for weeks. This effect has resulted in the expression “dobutamine holiday,” ie, animals with CHF spend 1-2 days in the hospital every month or so to receive a dobutamine drip. Other Therapy:
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Deficiency of L-carnitine has been documented in a family of Boxers with dilated cardiomyopathy, and supplementation resulted in an improvement in cardiac contractility. L-carnitine plays a pivotal role in fatty acid metabolism and myocardial energy production. The incidence of L-carnitine deficiency in the general population of dogs with dilated cardiomyopathy has not been determined. The cost of this compound, along with the fact that an endomyocardial biopsy is required to document deficiency, have limited the use of L-carnitine. Supplementation with coenzyme Q10 has resulted in rather dramatic increases in cardiac contractility in people with dilated cardiomyopathy who are receiving conventional therapy. Coenzyme Q10 is a member of the electron transport chain and is essential in myocardial energy production. The efficacy of coenzyme Q10 in dogs is being evaluated. Compensatory Mechanisms in Congestive Heart Failure Regardless of the underlying cause of heart failure, the body reacts to a decrease in cardiac output in a consistent manner. Through a vast network of baroreceptors, there is constant neural input regarding blood flow and pressure. When decreased flow or pressure is sensed, there is an immediate withdrawal of parasympathetic tone and activation of the sympathetic nervous system. These changes result in an immediate increase in heart rate and cardiac contractility as well as constriction of arterioles and veins. Decreased blood pressure along with increased sympathetic tone activates the renin-angiotensin-aldosterone axis. Renin is released by the juxtaglomerular apparatus of the kidney and converts angiotensinogen to angiotensin I, an inactive decapeptide. The two terminal amino acids of this peptide are cleaved by angiotensin-converting enzyme (an enzyme found in high levels in pulmonary endothelial tissue) to form angiotensin II, a remarkably potent vasoconstrictor. Angiotensin II also increases thirst, promotes sodium retention by the kidneys, and stimulates secretion of aldosterone by the adrenal cortex, resulting in further sodium and water retention. In the short-term, these compensatory mechanisms are beneficial and help to restore fluid volume and blood pressure. They are life-saving in animals with transient circulatory collapse (eg, hemorrhage) but become maladaptive when stimulated by chronic conditions (eg, heart disease). Sustained activation of the sympathetic nervous system increases myocardial oxygen demand, predisposes the heart to arrhythmias, and may cause myocardial damage (necrosis of myocytes). Persistent sodium and water retention hastens the development of pulmonary edema. Chronic vasoconstriction strains the heart by either increasing afterload or impeding ventricular emptying. As these compensatory mechanisms become deleterious, cardiac output decreases, further stimulating these processes, ie, the “vicious cycle of heart failure.” Clinical Manifestations of Heart Failure To rationally select appropriate therapy and provide an accurate prognosis, it is advantageous to categorize the type and stage the degree of heart failure. A system for staging heart failure in animals, developed by the International Small Animal Cardiac
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Health Council has three stages based on the following criteria: 1) Asymptomatic—heart disease is detectable, but there are no clinical signs. A cardiac murmur, arrhythmia, and radiographic changes may be present. 2) Mild to moderate heart failure—clinical signs of heart failure are evident at rest or with mild exercise. 3) Advanced heart failure— there are critical clinical signs including respiratory distress, marked ascites, and profound exercise intolerance. With each advancing stage, the prognosis worsens and the need for treatment increases. It is also important to determine whether the heart failure is left-sided, right-sided, or generalized. Therapy of Congestive Heart Failure Medical management of CHF is aimed at reversing or controlling the deleterious effects of the underlying disease. These effects may include pulmonary congestion and edema, cardiac arrhythmias, reduced cardiac output, and excessive vasoconstriction. In severely affected animals, specific medications may be needed to control each of these complications. See also systemic pharmacotherapeutics of the cardiovascular system, Systemic Pharmacotherapeutics Of The Cardiovascular System: Introduction. The Endocardium Infective Endocarditis: Infection of the endocardium typically involves one of the cardiac valves, although mural endocarditis may occur. It is thought that some sort of endothelial defect must be present for infective endocarditis to develop. When the endothelium is partially eroded and underlying collagen exposed, platelets adhere and produce a local thrombus. Bloodborne bacteria may become enmeshed in this thrombic lattice, resulting in a localized infection. This infection, through its own enzymes and host mediators, causes a progressive destruction of the valve, resulting in valvular insufficiency. In dogs, the aortic valve is most commonly affected, resulting in aortic insufficiency. The left ventricle cannot tolerate the constant back flow from the insufficient valve and soon fails. Infective endocarditis of the AV valves (tricuspid and mitral) also occurs but is better tolerated than aortic endocarditis. In horses, the mitral valve is most commonly affected, while the tricuspid valve is most frequently involved in cattle. In cats, infective endocarditis is rare, and there are no breed predilections. In dogs, German Shepherd Dogs and other large-breed dogs are typically affected; there is a significant predilection for males (72%), and the mean age is 5 yr. Bacteria released from the infected valve enter the circulation and colonize other organs; therefore, infective endocarditis can produce a wide spectrum of clinical signs that may be neurologic, GI, urologic, orthopedic, or cardiovascular in nature. A chronic, fluctuating fever is usually present. Shifting leg lameness may occur. Malaise and weight loss are present in almost all cases. If a right-sided valve is affected (tricuspid, pulmonic), ascites and jugular pulsations may be present. A murmur is present in most cases, the exact type depending on the valve involved. When there is aortic endocarditis, a soft diastolic murmur is present, heard best over the left heart base, and arterial pulses are bounding. Mitral endocarditis
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results in a murmur similar to that caused by degenerative valve disease, ie, a prominent systolic murmur heard best over the left cardiac apex. Bacteria most often isolated from affected small animals include Streptococcus , Staphylococcus , Escherichia coli , and Klebsiella . Other bacterial species and fungi may be involved. A precipitating infection (eg, dental disease, pyoderma, prostatitis) can be determined in ~60% of affected dogs. Streptococcus and Actinobacillus equuli are the most common isolates of horses. A complete blood count often shows a neutrophilic leukocytosis. An active infection may be associated with the presence of band neutrophils, and a chronic infection with a monocytosis (90% of cases in one series). Anemia of chronic disease is frequently present. Serum analysis abnormalities reflect organ involvement and may include increases in liver enzymes, BUN, and creatinine. A urinalysis will demonstrate an active sediment if pyelonephritis is present. Blood cultures with sensitivity should be obtained in affected animals. It is preferable to draw two or three blood samples 1-2 hr apart. A strict aseptic technique is required. Radiography demonstrates cardiac chamber enlargement, depending on the location of the involved valve. If the aortic or mitral valve is affected, there will be left atrial and left ventricular dilatation. Evidence of left-sided failure may be seen as an increase in the interstitial densities and an alveolar pattern in the lungs. If the tricuspid or pulmonic valve is affected, right-sided chamber enlargement is expected. Diskospondylitis is a common sequela of infective endocarditis in dogs and is characterized by irregular, lytic vertebral endplates. Echocardiography is the ideal test to definitively diagnose infective endocarditis. The affected valve is easily detected; the involved area is hyperechoic (bright) and thickened. Doppler echocardiography will confirm insufficiency of the valve. There will be chamber enlargement on the side of the affected valve. Electrocardiographically, there is normal sinus rhythm in most cases. Occasional to frequent atrial premature and ventricular complexes may occur. Infrequently, other arrhythmias such as atrial fibrillation or third-degree AV block are found. The height of the R waves may be increased (suggestive of left ventricular enlargement) and the width of the P wave increased (suggestive of left atrial enlargement). Therapy must be directed at controlling the CHF, sterilizing the lesion, and stopping spread of infection. The heart failure may be extreme and intractable if the aortic valve is involved; the prognosis is grave in these cases. The prognosis is much more favorable when infection is limited to one of the atrioventricular valves. Controlling CHF requires the use of diuretics (eg, furosemide), vasodilators (eg, enalapril), and digoxin if there is a rapid rate, supraventricular arrhythmias, or decreased contractility. Initially, parenteral antibiotics are indicated for 1-2 wk, followed by oral antibiotics for 6-8 wk. Bactericidal antibiotics should be used initially and changed, if needed, based on results of sensitivity studies. The most common combinations are ampicillin and gentamicin or cephalothin and gentamicin (renal function should be monitored). Unfortunately, most affected animals do not survive. Those that respond to therapy will likely require long-term cardiac medications (eg, diuretics, vasodilators, digoxin) and frequent reevaluations. Considering the poor clinical course, prevention is vital. When animals with coexisting
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heart disease are to be subjected to procedures with a potential to cause bacteremia (eg, dentistry), a broad-spectrum antibiotic should be administered (eg, ampicillin or amoxicillin 1 hr before the procedure and for 2-3 days after the procedure). Degenerative Valve Disease (Endocardiosis): This acquired disease is characterized by degeneration and fibrosis of the cardiac valves. As endocardiosis progresses, the affected valve becomes increasingly insufficient. Insufficiency of the mitral valve allows blood to jet back into the left atrium during ventricular contraction, which increases the pressure within the left atrium, which decreases venous flow from the lungs. This results in pulmonary venous congestion and ultimately pulmonary edema. In addition, as the left atrium dilates, the likelihood that atrial arrhythmias (atrial premature contractions, atrial fibrillation) will occur is high, further decreasing cardiac output. The constant jetting of blood from the high-pressure left ventricle physically damages the endocardium of the left atrium and, in chronic cases, may result in left atrial rupture. The decrease in the amount of blood ejected by the left ventricle (cardiac output) forces several compensatory mechanisms into action. The body responds to decreases in cardiac output by increasing sympathetic tone and activating angiotensin-converting enzyme (ACE). On a chronic basis, these compensatory mechanisms become deleterious rather beneficial. Chronic increased sympathetic tone causes sustained tachycardia, which increases the oxygen demand of the heart and predisposes to arrhythmias. ACE activation results in the formation of angiotensin II, which causes sustained arteriolar and venous constriction and release of aldosterone. Vasoconstriction increases the cardiac afterload, hampering ventricular ejection of blood. Aldosterone release results in sodium and water retention and predisposes to pulmonary edema. Endocardiosis is the most common cardiac disease in veterinary medicine. It most commonly affects the left AV (mitral) valve in horses, dogs, and cats, but the disease is uncommon in cats. In horses, degenerative valve disease often affects the aortic valve and consists of valvular nodules or fibrous bands at the free borders of the valve. This condition is most common in middle-aged and old horses and causes a prominent (grade 2-6) holodiastolic murmur heard best at the left fourth intercostal space. This murmur often has a highpitched or musical quality. In most cases in horses, unlike in dogs, clinical signs are uncommon because significant left ventricular volume overload and dilatation do not occur. Echocardiography is used to confirm the diagnosis and allows visualization of the valvular nodules, fibrous band lesions, and valvular prolapse. Treatment is seldom necessary due to the slow progression of the disease and the ability of the horse to tolerate aortic regurgitation. About 60% of dogs >8 yr old are affected. Endocardiosis occurs primarily in smallbreed, older dogs, particularly Miniature Poodles, Shetland Sheepdogs, Lhasa Apsos, Dachshunds, and Cocker Spaniels. The severity of clinical signs depends on the degree and chronicity of the valvular disease. Early in the course of the disease, there are no clinical signs present, although a systolic murmur of low intensity (grade 1-2) can be
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heard at the left apex. As the disease progresses, exercise intolerance and respiratory rate gradually increase, followed by coughing and labored breathing. In general, with continued progression, the intensity of the murmur increases (up to grade 6) and a precordial thrill develops. A complete blood count, serum chemistry profile, and urinalysis are usually within normal limits. Radiographically, left atrial enlargement is the characteristic finding. Other changes include enlargement of the left ventricle and the pulmonary veins. As heart failure develops, interstitial densities increase progressively, and ultimately air bronchograms appear, which are indicative of an alveolar pattern and severe pulmonary edema. Echocardiography reveals a thickened, enlarged, and irregular valvular leaflet of normal echogenicity. Chordae tendineae may be ruptured, and the AV leaflets may prolapse into the atrium during ventricular contraction. Ventricular enlargement is common. In most cases, contractility appears normal to exaggerated as the left ventricle is able to eject a significant portion of blood into the left atrium rather than the high-pressure aorta. A decrease in contractility signals the presence of myocardial failure. Electrocardiographically, the rhythm in most cases is normal sinus rhythm or sinus tachycardia. When congestive heart failure (CHF) occurs, sinus arrhythmia converts to a regular sinus rhythm and the rate increases. Left atrial enlargement promotes the occurrence of atrial arrhythmias such as atrial premature complexes and atrial fibrillation. Cardiac hypoxia causes ventricular arrhythmias— ventricular premature contractions are common when CHF is present. There may be evidence of left atrial enlargement (P-mitrale or widened P waves) and left ventricular enlargement (tall and widened R waves) when the mitral valve is involved. The essentials of treatment are to slow the progression of clinical signs early with vasodilators, to control pulmonary edema when it occurs with vasodilators and diuretics, and to reduce the heart rate and increase contractility later in the course of the disease when vasodilators and diuretics begin to lose their effectiveness. Optimal therapy should be planned for each stage of disease. Affected dogs can live for years with clinical signs of degenerative valve disease and proper treatment. Stage 1: A soft (grade 1-2) systolic murmur is present, but there are no clinical signs of heart failure and the left atrium is not enlarged radiographically. No cardiac medications are indicated. The owner should be instructed to avoid feeding any foods or snacks high in sodium. Stage 2: A systolic murmur (grade 2-3) is present, there are no clinical signs, yet the left atrium is enlarged radiographically. Vasodilator therapy (eg, enalapril at 0.4-0.5 mg/kg, s.i.d.) will likely be beneficial. Owners should avoid feeding excessive sodium—a diet specifically formulated for older animals is ideal. Stage 3: A systolic murmur (grade 3-4) is present, and there is cough at night and after activity. There is left atrial enlargement radiographically. Vasodilator therapy should be continued (eg, enalapril, dose increased to 0.4-0.5 mg/kg, b.i.d.). Furosemide should be
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started at 1 mg/kg, s.i.d. to b.i.d., and the lowest effective dose determined. The animal should be fed a diet specifically formulated for older animals. Stage 4: A loud (grade 4-6) systolic murmur is present. There are signs of heart disease, ie, exercise intolerance and cough, through the day. Radiographically, left atrial enlargement is moderate to marked. The heart rate is increased. Enalapril (0.5 mg/kg, b.i.d.), furosemide (1-2 mg/kg, s.i.d. to b.i.d.), and digoxin (0.22 mg/m 2) are indicated. A diet moderately restricted in sodium should be part of the therapy. Valvular Blood Cysts or Hematomas: These benign valvular lesions are present in up to 75% of calves <3 wk old. They are most commonly located on the AV valves. The Myocardium The myocardium is affected by a variety of disease processes, including primary muscle disorders (eg, dilated or hypertrophic cardiomyopathy), degenerative and inflammatory diseases, neoplasia, and infarction. The myocardium is also sensitive to various toxins, including adriamycin, oleander, and fluoroacetate (1080). Myocarditis occurs in all species and may be caused by viral, bacterial, parasitic, or protozoal infection. Canine parvovirus, encephalomyocarditis virus, and equine infectious anemia are viruses with a propensity to cause myocarditis. Myocardial degeneration occurs in lambs, calves, and foals with white muscle disease and in pigs with mulberry heart disease or hepatosis dietetica. Mineral deficiencies (eg, iron, selenium, and copper) can also result in myocardial degeneration. Dilated Cardiomyopathy: This acquired disease is characterized by the progressive loss of cardiac contractility of unknown cause. Several forms of secondary dilated cardiomyopathy exist (cause known); for example, it can be due to a taurine deficiency in cats or induced by adriamycin or parvovirus. As cardiac contractile function is progressively lost, cardiac output decreases. Increased blood volume and pressure within the chambers causes them to dilate, most dramatically evident in the left atrium and left ventricle. In response to the decreased contractility and cardiac output, the sympathetic nervous system and the renin-angiotensin-aldosterone axis are activated. As in degenerative valve disease, these compensatory mechanisms, although initially beneficial, become deleterious when chronically activated. Constant stimulation of the heart by the sympathetic nervous system causes ventricular arrhythmias and myocyte death, while constant activation of the renin-angiotensin-aldosterone axis causes excessive vasoconstriction and retention of sodium and water. In most cases, signs of left-sided congestive heart failure are seen, although signs of right-sided failure (ascites) can develop. Dilated cardiomyopathy is common in large-breed dogs and rare in small-breed dogs (English Cocker Spaniel is an exception). Doberman Pinschers, Great Danes, German Shepherd Dogs, and Labrador Retrievers are particularly at risk. The disease is typically seen in middle-aged dogs, with males affected more than females. The incidence in cats
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has dropped dramatically since the discovery in 1985 that taurine deficiency was responsible for most cases. Since then, taurine levels have been increased to acceptable levels in all commercial cat foods. Most cases today are not taurine responsive and reflect a primary (or idiopathic) disease. In cats, there is no breed predilection. Most often, dogs and cats develop signs acutely. Signs include exercise intolerance, inappetence, weight loss, cough, weakness, and syncope. Dogs with predominately right-sided failure usually have a more chronic course, with signs including weakness, exercise intolerance, and ascites. A soft systolic murmur, best heard at the left cardiac apex, is usually present. In addition, a third heart sound or gallop is also frequently present, especially in cats. A complete blood count, serum chemistry profile, and urinalysis are usually within normal limits. Radiographically, there is mild to marked generalized cardiomegaly. If heart failure is present, the interstitial densities are increased and the pulmonary veins enlarged. Echocardiography is the ideal test to definitively diagnose dilated cardiomyopathy. There is a dramatic loss of cardiac contractility (reported as a low fractional shortening). Cardiac chambers, especially the left atrium and left ventricle, are dilated. There are no significant valvular lesions, although mitral insufficiency may develop as the cardiac dilatation separates the mitral valve leaflets. Electrocardiographically, the rhythm in most cases is normal sinus rhythm to sinus tachycardia. Ventricular premature complexes are common, especially in Doberman Pinschers and Boxers. Atrial premature complexes and atrial fibrillation are also common. There may be electrocardiographic evidence of left atrial enlargement (P mitrale or widened P waves) and left ventricular enlargement (tall and wide R waves). Conduction disturbances, such as left bundle branch block, are uncommon. The occurrence of one or more ventricular premature contractions in a presumed healthy Doberman Pinscher is highly suggestive of dilated cardiomyopathy. The objectives of therapy are to control the congestive state (eg, with diuretics), to improve contractility (eg, with digoxin, dobutamine), and to reduce cardiac stress (eg, with vasodilators). Some animals benefit from supplementation with L-carnitine, taurine, or coenzyme Q10. When congestive heart failure is severe, diuretic therapy should be aggressive, eg, furosemide at 4-6 mg/kg, IV, with a repeat dose 4 hr later. Oxygen supplementation should also be provided, either through an oxygen cage or by nasal insufflation. Nitroglycerin ointment is also indicated. A combination dobutamine and sodium nitroprusside infusion is often beneficial. As the pulmonary edema resolves, furosemide is administered PO (rather than IV), and oxygen therapy and nitroglycerin are continued. Treatment with digoxin should also be initiated (for large-breed dogs at 0.22 mg/m2, b.i.d.). Vasodilator therapy is definitely indicated; enalapril is the preferred drug and should be administered at 0.5 mg/kg, b.i.d. Other ACE inhibitors, such as captopril and benazepril, can be used but are not approved for use in dogs. L-carnitine will help a few dogs, but a dog deficient in L-carnitine cannot be identified without an endomyocardial biopsy; in addition, the supplement may be cost prohibitive. Coenzyme Q10 supplementation has resulted in significant improvements in people with dilated
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cardiomyopathy, and its efficacy in dogs is being evaluated. The recommended dose is 30 mg, t.i.d. Administration of fish oil was recently shown to reduce the severity of cardiac cachexia in Doberman Pinschers with dilated cardiomyopathy. Antiarrhythmic therapy is also frequently indicated, especially for Doberman Pinschers and Boxers. Routine, or preferably continuous, ambulatory electrocardiography is indicated to determine the type and frequency of the arrhythmia and the effect of the antiarrhythmic agent. Procainamide, propranolol, and tocainide are most commonly used. The prognosis is guarded to poor for most dogs. The prognosis is worst in Doberman Pinschers, with most dying within 2 mo of diagnosis. The prognosis is better for dogs exhibiting predominately signs of right-sided failure, with some surviving for 1-2 yr. Hypertrophic Cardiomyopathy: This is the most common cardiomyopathy in cats. It is characterized by left ventricular hypertrophy in the absence of a precipitating cause (such as hypertension or aortic stenosis) and is typically seen in middle-aged cats. Although contractility is not significantly impaired, the hypertrophic ventricular walls lose compliance and resist filling during diastole (diastolic failure). This increases pressure within the left atrium, causing it to dilate; the pressure is then transmitted to the pulmonary veins, causing pulmonary edema. Stasis of blood often occurs in the markedly dilated left atria, predisposing affected cats to aortic thromboembolism. Middle-aged male cats are primarily affected and often develop acute dyspnea, collapse, or hindlimb paresis. Abnormal heart sounds are frequently present and include soft to prominent heart murmurs and gallop rhythms. Increased bronchovesicular sounds and rales are suggestive of pulmonary edema. Pulses may be weak, normal, or absent if thromboembolic disease is present. Radiographically, there is pronounced left atrial enlargement and variable left ventricular enlargement. Evidence of pulmonary edema is frequently present, and pleural effusion is occasionally seen. Echocardiography is the test of choice and allows confirmation of the disease as well as the need for additional therapy (eg, anticoagulant therapy is most beneficial in cats with severe left atrial enlargement). Contractility is usually within normal limits or excessive. A variety of electrocardiographic abnormalities may be present, including atrial premature complexes, ventricular premature complexes, and ventricular tachycardia. Treatment must control pulmonary edema, improve diastolic function, and reduce incidence of systemic thromboembolism. Furosemide and nitroglycerin are indicated when acute pulmonary edema is present. Diltiazem (7.5 mg, t.i.d.), a calcium-channel blocker, improves diastolic function. Vasodilators are occasionally used. Recently, enalapril has been demonstrated to reduce left ventricular hypertrophy and left atrial enlargement in affected cats. Either aspirin (10 mg/kg, every third day) or warfarin (0.20.5 mg, daily) is used to reduce the chance of thrombus formation. Myocardial diseases are infrequently reported in horses. Streptococcus is the most common bacterial cause of myocarditis. Salmonella , Clostridium , equine influenza, equine infectious anemia, Borrelia burgdorferi , and strongylosis have also been incriminated. Deficiencies of vitamin E or selenium are known to cause myocardial
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necrosis. Cardiac toxins include ionophore antibiotics such as monensin and salinomycin, cantharidin (blister beetle toxicosis), Cryptostegia grandiflora (rubber vine poisoning), and Eupatorium rugosum (white snake root poisoning). These diseases cause typical signs of congestive heart failure—exercise intolerance, tachycardia, and tachypnea. In horses, signs of right-sided heart failure are common and include ascites, venous congestion, and jugular pulsations. A murmur of mitral or tricuspid regurgitation is usually audible as well as an irregular rhythm. Atrial fibrillation is common, and ventricular or atrial premature complexes may also be seen. Echocardiography reveals chamber dilation and poor contractility with essentially normal valves. A neutrophilic leukocytosis and hyperfibrinogenemia are common. Cardiac isoenzymes (creatine kinase and lactate dehydrogenase) are often increased. Treatment should be aimed at improving cardiac contractility, relieving congestion, and reducing vasoconstriction. Digoxin and dobutamine are used most commonly to improve contractility. Furosemide is indicated to control signs of pulmonary edema. Corticosteroids are often used when cardiac isoenzymes are increased and a viral infection is deemed unlikely. Pericardial Effusion When fluid accumulates within the pericardial sac, the pressure within the sac increases and progressively compresses the chambers of the heart. Because the rightsided chambers have thinner walls than the left-sided chambers, they are compressed to a greater degree. Compression of the right-sided chambers has two major consequences: venous return is significantly decreased, causing jugular venous distension and ascites, and blood flow to the lungs is significantly decreased, causing hypoxia and tachypnea. Once the pericardial pressure equals or exceeds the cardiac chamber pressures, the condition is referred to as cardiac tamponade. If not treated, cardiac tamponade will result in cardiovascular collapse and death. Pericardial effusion (hydropericardium)is uncommon compared with other acquired cardiovascular diseases but is not rare. It occurs in both small and large animals. There are no breed predilections in cats. Labrador Retrievers and Golden Retrievers are the most commonly affected breeds of dogs. Overall, most cases involve large- and giantbreed dogs (90%), and there is a predilection for males (62%). The severity of clinical signs depends on the rate of pericardial fluid accumulation. Historical features include exercise intolerance, inappetence, listlessness, and abdominal swelling. In horses, there is often a history of respiratory tract infection, fever, anorexia, and depression. Physical examination findings include lethargy, jugular venous distention, muffled heart sounds, and occasionally pericardial friction rubs. Ascites is consistently present in affected dogs. The two most common causes are neoplastic (hemangiosarcoma, heart-based tumor) and idiopathic or benign. Less common causes are infectious (feline infectious peritonitis in cats), trauma, chamber rupture, and secondary to congestive heart failure. Cattle most often develop pericardial effusion
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secondary to traumatic reticuloperitonitis or lymphoma. In horses, septic and idiopathic are the most common types reported. Results of a complete blood count, serum chemistry profile, and urinalysis are usually within normal limits. A mild anemia, neutrophilic leukocytosis, hyperfibrinogenemia, and hyperproteinemia may occur in horses with septic pericarditis and effusion. Cytologic evaluation of the pericardial fluid can be misleading if the effusion is serosanguinous (95% of all canine effusions). In benign effusions, activated mesothelial cells resemble neoplastic cells, and a false positive may be reported. Conversely, neoplastic cells rarely exfoliate; therefore, a false negative report is likely in cases of neoplastic effusion. In horses with suspected septic pericarditis, a culture and sensitivity of the fluid should be performed. In septic pericarditis, there will be a large number of neutrophils, some degenerated. Protein content of the fluid will be high, and bacteria may be seen. Cytologic features of idiopathic pericardial effusion in horses are variable, with neutrophils, eosinophils, and macrophages present in variable numbers. Radiographic findings include an increase in the size of the cardiac silhouette, which takes on a roundish shape (there is a loss of contour caused by the cardiac chambers). The caudal vena cava is dilated. The interstitial density is increased—not from pulmonary edema but secondary to loss of lung volume caused by the enlarged pericardial sac. Echocardiography is the ideal test to definitively diagnose pericardial effusion. A tumor can be visualized in many cases of neoplastic effusion, but not all. When cardiac tamponade is present, the walls of the right atrium and right ventricle appear to collapse and flutter. The left-sided chambers are often decreased in size secondary to poor return from the lungs. Echocardiography can be used to guide the catheter during pericardiocentesis and to confirm that the effusion is absent after pericardiocentesis. Electrocardiographically, the rhythm in most cases is normal sinus rhythm to sinus tachycardia. Occasional atrial premature and ventricular complexes may occur. The height of the R waves is often decreased (<1 mV), and there may be a pattern of alternating heights of the R waves, referred to as electrical alternans. This electrocardiographic feature is virtually pathognomonic for pericardial effusion and results from the swinging motion of the heart within the fluid-filled pericardial sac. Animals with cardiac tamponade should receive urgent treatment. The only effective treatment is pericardiocentesis, ie, removing the effusion with a catheter. Cardiac medications have no role. Diuretics are contraindicated because they decrease blood volume and cause further collapse of the cardiac chambers. The dog should be sedated to allow full recovery of the effusion. The catheter should enter the chest on the right side, just above the costochondral junction at the fourth to fifth intercostal space, and a syringe or extension set with stopcock and syringe (latter preferred) attached. The system must be closed to avoid a pneumothorax. The catheter should be passed directly towards the heart while intermittently aspirating. When the pericardial sac is entered, fluid (usually hemorrhagic) will flow freely into the syringe. The catheter should be carefully advanced over the needle into the pericardial sac. If arrhythmias develop,
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withdrawing the needle slightly usually suffices. Antiarrhythmic therapy is rarely needed. As much fluid as possible should be removed, and a sample placed into an EDTA tube for analysis. When performing pericardiocentesis in the horse, it is recommended that the left fifth intercostal space be used. This side is preferred to avoid the atria, coronary arteries, and right ventricle. Postpericardiocentesis lavage, with or without antibiotics, is often performed in horses. Pericardiocentesis is easily performed and relatively safe, even for novices. A reluctance to perform this procedure because of inexperience should be tempered with the knowledge that medications are ineffective and contraindicated. However, confirming the presence of pericardial effusion echocardiographically, if possible, is advisable before performing pericardiocentesis. Broad-spectrum antibiotics and parenteral fluids may be given immediately before and after pericardiocentesis. Corticosteroids have not been reported to play a beneficial role in benign pericardial effusion in dogs, although they have been used with success in horses. Most tumors that cause neoplastic effusion are nonresponsive to chemotherapy. When benign effusion is suspected (ie, no mass visible by echocardiography), the owner should be instructed to carefully monitor the animal for any signs of recurrence. Should this occur, a repeat pericardiocentesis is indicated. It is generally recommended that surgical exploration be performed if the condition recurs again. Heartworm Disease: Introduction (Dirofilariasis) Dirofilaria immitis has a worldwide distribution and infects a wide variety of species (dog, cat, ferret, fox, wolf, sea lion, horse). The distribution is influenced by a reservoir population of animals (dogs usually) in which the life cycle is completed and microfilaremia occurs and by a mosquito vector in which the early larval stages develop. Different mosquito feeding patterns influence the areas and species of animal infected. For transmission to cats, the mosquito must first feed on a dog and then, after adequate warm environmental exposure, feed on a cat. Life Cycle and Pathogenesis: Adult female (~27 cm long) and male (~17 cm long) heartworms normally reside in the pulmonary arteries and right ventricles without significantly interfering with blood supply. Microfilariae (~315 µm long and 6-7 µm wide) are discharged into the bloodstream and survive 1-3 yr. The number of circulating microfilariae in dogs is increased in warm ambient temperature, after eating, and late at night. The microfilariae are ingested by a mosquito during feeding. Within the mosquito, the larvae (L1) migrate to the stomach and then to the mouthparts (L3) during development. Adequate exposure to warm temperatures must occur during the relatively short life span (1 mo) of the mosquito, and the rate of development of the larvae, which varies depending on the temperature, can be as short as 8 days at 30°C or as long as 28 days at 1-8°C. When the mosquito feeds again, the infective L 3 are deposited on the skin of the animal and enter through the bite wound. A single mosquito can transmit up to 10-12 L3.
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The L3 stages molt and migrate to the pulmonary arteries ~100 days after infection, during which time they develop to L5 (1-2 cm long). The L5 are found mainly in the caudal distal pulmonary arteries; over the next 2-3 mo, they develop to mature adult heartworms and migrate back toward the right ventricle. If both sexes of adults are present, microfilariae are produced 6-7 mo after the animal was infected with L3. Adult heartworms can live 3-5 yr. Although an endarteritis develops, embolization and vascular occlusion is rare when the worms are alive. The severity of the pathology is influenced not only by the number of worms but also by the shear stress of high blood flow associated with exercise. Severe pathology can occur in athletic dogs with low worm burdens. The classically described cor pulmonale syndrome is seen only in dogs with an exercise pattern forcing right ventricular hypertrophy from increased cardiac outputs and increased pulmonary vascular resistance. In endemic areas, the average worm burden is ~15 worms in dogs and 1-3 worms in cats. In cats and ferrets, respiratory failure can be associated with infection with a single worm. High worm burdens can be found in dogs with minimal cardiac changes if the dog is sedentary. High worm burdens (>75) also can be demonstrated in acute postcaval syndromes and chronic ascites from tricuspid valve dysfunction. Because many animals develop increased resistance from repeated exposure to L3 over time, high worm burdens are most likely to occur in dogs that have not been exposed previously to any mosquitoes with L3 and are then bitten by many mosquitoes over a 3-mo period. Clinical Findings: The clinical signs of heartworm disease depend on the stage of the life cycle, the severity of infection, and the host response to infection. The initial arrival of L5 in the small vessels of the lungs is associated with an intense eosinophilic reaction and a diffuse radiographic pattern. The animal may begin to cough 2-3 mo before microfilariae are produced and antigen begins to circulate. Clinical diagnosis at this early stage of disease is difficult, especially in cats and ferrets. An active dog may develop exercise intolerance because of decreased cardiac output. Nonspecific signs of weight loss, fever, and dyspnea can occur in severe disease. Ascites may develop in right-sided heart failure from cor pulmonale or from mechanical dysfunction of the tricuspid valve as in postcaval syndromes. Many dogs and cats are asymptomatic, although subclinical disease may decrease their quality of life. In ~10% of dogs with heartworms, an intense immune reaction by the host clears the microfilariae; severe pulmonary reactions are seen, and coughing is the primary clinical sign. No pathology has been associated with circulating microfilariae. Clinical signs in cats are primarily intermittent respiratory disease (coughing or dyspnea) or sporadic vomiting not associated with eating. The respiratory signs mimic those of bronchial asthma and initially respond to corticosteroid administration. Cats may present with acute dyspnea or collapse with no previous respiratory signs. In these cases, which are often confused with bronchial asthma, acute death is common. Other clinical signs associated with acute disease in cats include convulsions, vomiting and diarrhea, blindness, tachycardia, and syncope. Initial respiratory signs often occur 4-6
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mo after the peak mosquito season. Nonspecific signs of weight loss and anorexia without respiratory or GI signs occur in some cats. Right-sided heart failure is rare in cats and is usually associated with a high worm burden (more than seven worms). Diagnosis: Diagnostic testing for dirofilariasis includes a complete blood count, Knott's test, thoracic radiographs, fecal examination, ECG, immunofluorescent antibody (microfilariae), ELISA-adult antibody (cats only), ELISA-adult antigen, tracheal wash, and arteriogram. Concentration techniques (modified Knott's and filter tests) successfully demonstrate microfilariae in a blood sample in ~60% of dogs and <10% of cats with heartworms. Because microfilariae survive after adult worms have died, a small percentage of dogs can have microfilaremia but no adults in the heart. In addition, puppies born to bitches with a high microfilariae count can have a transient microfilaremia that cannot become an adult infection. Microfilariae of D immitis should be differentiated from those of the nonpathogenic filarids D repens and Dipetalonema reconditum on the basis of morphology and staining characteristics with acid phosphatase. Occult infections, in which the animal is amicrofilaremic, can be seen when the infection is due to immature (<6 mo old) worms, a single worm, or worms of all the same sex. Occult infections can also result from host immunologic reactions to microfilariae or from iatrogenic infection. Monthly preventive medications will induce embryo stasis in the female heartworm, and occult infections have been demonstrated in most heartworm-positive dogs after many months of medication. Therefore, antigen testing is necessary to determine the heartworm status of a dog that has been on monthly preventive medication. Circulating adult antigen can be detected before or after the initial microfilaremia. The detection of circulating antigen is based on a laboratory-derived antibody binding to an adequate amount of circulating heartworm antigen. Although the glycoprotein detected by most assays is found throughout the parasite, the major source of circulating antigen is the reproductive tract of the mature female heartworm. The maturity and number of females influences the amount of antigen. Animals with immature worms and low worm burdens (especially cats) will be antigen negative—even when worms are present in the pulmonary arteries and clinical signs are present. Thoracic radiographs can be a screening tool for dogs and cats with clinical signs suggestive of heartworm disease. In dogs, the pulmonary arteries can be tortuous and enlarged, with an enlarged pulmonary arterial segment at the 1 o'clock position on a ventrodorsal view. Right ventricular enlargement may not be noted if the hypertrophy has not been induced by physical activity or severe vascular lesions. The pulmonary parenchymal changes can be diffuse in early L5 infection but also can become granulomatous in chronic severe infections. In cats, cardiac changes are rare, and even an enlarged pulmonary arterial segment on the ventrodorsal view is not visible beyond the cardiac shadow. Enlarged caudal pulmonary arteries are the most consistent lesion in cats with
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heartworms. Severe lung parenchymal changes may obscure the vascular pattern. A fluid density lung lobe is associated with acute signs in cats and may be confused with a consolidating pneumonia. Echocardiograms are diagnostic, with typical “double parallel” white lines noted in the pulmonary arteries or right ventricles of dogs or cats. Echocardiograms are especially useful in diagnosis of postcaval syndromes and ascitic conditions associated with heartworm disease. The typical right axis deviation and deep S waves are seen on an ECG only if right ventricular hypertrophy is significant. Tracheal cytology is usually nonspecific and is rarely positive for bacteria in either dogs or cats. An eosinophilic cytology is usually a stage-specific reaction. Complete necropsy with thorough examination of the distal pulmonary arteries may be required to demonstrate heartworms in cats. Treatment in Dogs: Steps to manage treatment of dogs infected with heartworms consist of the following: 1) diagnostic evaluations (before therapy) to determine subclinical disease, especially of the liver and kidneys; 2) adulticidal therapy to eliminate mature worms; 3) a rest period of 4-6 wk to allow the dog to recover from the lung injury associated with worm death; 4) microfilaricidal therapy if required; 5) a test for microfilariae to determine success of microfilaricidal therapy; 6) an antigen test to determine success of adulticidal therapy; and 7) preventive medication. Use of aspirin, aspirin and dipyridamole, serotonin antagonist, short-acting heparin, and high-dose corticosteroids to decrease the clinical significance of heartworm lesions has been unsuccessful. Abnormal pressor vessel dynamics and pulmonary parenchymal damage may contribute to the failure of these agents. Because of the pressure overload of heartworm disease, treatment with digitoxin is usually not recommended. An angiotensin-converting enzyme inhibitor may be used in severe right ventricle hypertrophy. The interstitial edema associated with acute signs of worm death is not aided by diuretic therapy. Adulticidal therapy eliminates the adult heartworms and allows repair of damage where fibrosis has not occurred. Death of the worms (either spontaneous or induced) in both dogs and cats is associated with severe parenchymal lung damage, and limitation of exercise is critical after adulticidal therapy. Platelet consumption and coagulopathies develop in most dogs 2-3 wk after adulticide treatment. Thiacetarsamide (2.2 mg/kg, four IV doses over 2 days) will kill most male and some female worms but has poor efficacy against immature and young female worms. Arsenical toxicity cannot be predicted in clinically normal dogs based on laboratory tests. Melarsomine (2.5 mg/kg, two IM doses over 24 hr) has improved efficacy (>95% kill). However, increased worm death can cause serious complications in dogs with high worm burdens. One IM dose followed 1 mo later by two IM doses is a safer alternative in dogs with severe heartworm disease or high antigen loads, which suggest large worm burdens. No agent has been successful as a pretreatment in decreasing the complication rate. Dogs should be rested for 4-6 wk.
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Complications of worm death often include impaired pulmonary function and vessel damage, which may initiate disseminated intravascular coagulation (DIC). A platelet count <100,000/µL is not uncommon, but an activated clotting time should be performed to determine if DIC is present (if so, the prognosis is poor). Dyspnea after adulticidal therapy is an emergency. Nasal oxygen and an immediate-acting glucocorticoid at doses used in shock are needed to provide adequate oxygenation and decrease the acute lung injury. Many dogs will respond within 24 hr. Because of the fragile nature of the capillary beds of the lungs, no exercise or stress should be allowed during this time. Currently, there are no FDA-approved drugs for microfilaricidal therapy. However, ivermectin at 50 µg/kg or milbemycin at the preventive dose is effective within 2-3 wk. Most microfilariae are killed quickly, and reactions, which usually occur within 1 hr of administration, are associated with high microfilariae counts in small dogs. Concentration techniques should be used to assess microfilarial status. Antigen assays 12-16 wk after successful adulticidal therapy should be negative. However, low worm burdens and immature worms can still be present with a negative antigen test. Positive antigen tests should be rechecked in 1 mo before initiating a second adulticidal regimen. Treatment in Cats: After the diagnosis has been confirmed, the therapeutic options must be carefully considered. Because feline heartworm disease can result in no signs or signs such as chronic vomiting or intermittent respiratory signs, owners often think the disease is less severe than it is. Without treatment, acute complications and death occur in a small percentage of cats. However, in asymptomatic cats, this risk appears to be small compared with the potential complications of adulticidal therapy. In addition, the life span of the adult heartworm is shorter in cats than in dogs, and spontaneous recovery is possible. However, adulticidal therapy has been used safely in cats and should be considered for cats with recurrent dyspnea that is life-threatening or with clinical signs that are unacceptable to the owner. Treatment of feline heartworm disease with thiacetarsamide sodium (2.2 mg/kg, given slowly IV, b.i.d., for 2 days) is tolerated by cats without immediate complications of hepatotoxicity or renal toxicity. However, pulmonary edema has been seen, and oxygen therapy and corticosteroids should be considered if dyspnea or cyanosis occurs. The use of ketamine as a sedative to aid in careful administration of thiacetarsamide is recommended in active cats. In symptomatic cats, clinical signs tend to improve after therapy. Chronically anorexic cats may require hyperalimentation. Although the presence of circulating microfilariae is uncommon, dithiazanine iodide and levamisole hydrochloride have both been used successfully as microfilaricides. Complications after therapy are more severe in cats than in dogs and are usually related to embolization. Sudden death from embolization can occur, especially within the first 10 days after adulticidal therapy. Embolization can result in severe lung
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infarction, hemoptysis, and dyspnea. Severe thrombocytopenia has not been noted. Based on the assumption that heartworm mass is related to antigen load, a cat with a “strong positive” antigen test would be more likely to develop complications after adulticidal therapy than a cat that has a low worm burden and is antigen negative or “weakly positive.” Embolization most often affects the caudal lung lobes, and thoracic radiographs may demonstrate a lung lobe with increased density. Oxygen therapy is indicated if hypoxemia or dyspnea occurs. High doses of corticosteroids (eg, prednisolone at 1-2 mg/lb, t.i.d.) with careful IV fluid therapy will often support the cat through the crisis. However, the routine use of corticosteroids before or after thiacetarsamide administration is not recommended in cats. There is evidence that aspirin may inhibit prostaglandin formation and thus increase leukotriene production in the lungs; the result would be bronchospasm and pulmonary hypertension. Aspirin is not currently recommended for use in feline heartworm disease, and it may be contraindicated when acute embolization occurs. The peracute nature of the postadulticidal reaction dictates that the cat be under constant surveillance, especially during the first 2 wk. The clinical and radiographic signs of acute embolization can resolve over 1-2 days. However, death can be so rapid that it occurs before therapy can be instituted. In asymptomatic cats, the risk and severity of the postadulticidal reaction and the resultant embolization is probably greater than that from the spontaneous death of heartworms. Unfortunately, the efficacy of thiacetarsamide cannot often be evaluated in cats because of the occult nature of the disease. However, in some cats that have had microfilariae, repeated attempts to eliminate microfilariae have failed and repeated adulticidal therapy has been required. If a cat was antigen positive before therapy, the antigen test should be negative 12 wk after adulticide therapy; a positive test would indicate that adult heartworms are still present. Melarsomine has not been evaluated in cats for routine clinical use. When adulticidal therapy is not done, such as in cats with intermittent clinical signs, owners should be educated about the nature of the peracute signs of embolization. An emergency dose of prednisolone (5 mg/kg) should be dispensed to be administered PO if collapse or dyspnea are noted. The onset of acute respiratory signs in a cat with heartworm disease is an emergency, and immediate treatment is needed. The radiographic signs of severe lung pathology should not be interpreted as consolidation or pneumonia. Oxygen therapy, cage rest, small volumes of IV fluids, and injectable prednisolone have resulted in clinical improvement and resolution of radiographic signs within 24 hr in some cats with life-threatening dyspnea and collapse. Prevention: In dogs, diethylcarbamazine (DEC), ivermectin, and milbemycin oxime are orally administered preventives. Dogs >6 mo old should test negative for microfilariae and antigen assay before preventive medications are administered. Dogs <6 mo old can be started on preventive medication but should be tested for microfilariae and antigen 6 mo
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to1 yr later. DEC is administered daily from 1 mo before to 2 mo after the mosquito season. Ivermectin and milbemycin oxime are administered once monthly from 1 mo after the onset to 1 mo after the end of the mosquito season. In temperate areas, preventive medications can be used year round. Dogs on monthly preventive should have antigen assays to determine their heartworm status. Preventive medications should not be administered to dogs that test positive for microfilariae. In cats in areas highly endemic for heartworm disease in dogs, the incidence of heartworms (20%) would indicate that preventives are warranted. In nonendemic areas, the incidence is not sufficient to warrant preventive therapy in cats. In endemic areas, it is suggested that preventive medication (ivermectin at 25 µg/kg or milbemycin at 50 µg/kg, administered PO once a month) be administered at 4-6 wk of age and continued for the life of the cat. Although incidence of heartworm disease is low in many areas and heartworm disease can be self-limiting in many cats, the high rate of complications associated with feline heartworm disease and the potential to initiate inflammatory lung disease and predispose to bronchial asthma may prove to be adequate indications for preventive medications.

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