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Veterinary Medicine

Arterial thromboembolism in the cat

Cats with any form of cardiomyopathy have a predilection to form intracardiac thrombi in the left atrium; the incidence is highest in cats with hypertrophic cardiomyopathy. These thrombi often become lodged at the bifurcation of the iliac arteries; less frequently they may occlude the brachia!, coeliac or renal arteries.

Pathophysiology

Altered blood flow and vascular stasis predispose to thrombus formation. Localized release of vasoactive substances such as serotonin and thromboxane at the site of vascular occlusion result in vasoconstriction of the collateral blood supply adjacent to the occluded vessel. Moreover, the release of serotonin induces platelets to aggregate which further potentiates clot formation. Occlusion at the iliac bifurcation (a so called *saddle* thrombus) results in ischaemic damage to the muscles and nerves of both hind limbs (ischaemic neuromyopathy).

Clinical signs

Iliac thrombosis is characterized by the sudden onset of crying and hindlimb paresis which results in dragging of one or both hind limbs (occlusion of a brachial artery may cause similar signs in a fore limb). The cat may present with acute dyspnoea and mouth breathing and the mucous membranes may appear cyanotic (particularly if a pulmonary artery is thrombosed). The affected muscles become firm and painful to touch after 24 hours. One or both femoral pulses may be absent and the paws and distal limbs are hypothermic (pink pads may appear pale).

Diagnosis

Diagnosis is usually based on the history and clinical signs. Since most cases of iliac thrombosis are associated with cardiomyopathy echocardiography should be performed as soon as the cat is stabilized. Non-selective angiocardiography may be helpful to determine the extent of the thrombosis and also the integrity of the collateral blood supply. Acute muscle damage results in increased plasma concentrations of aspartate aminotransferase (AST) and creatine kinase (CK). Urea and creatinine concentrations may increase after embolization of a renal artery.

Since the clinical signs of iliac thrombosis resemble those of lower motor neurone paralysis, spinal cord lesions, for example, acute spinal cord trauma, intervertebral discprotrusion (rarein the cat) or haemorrhage, and intravertebral tumours (lymphosarcoma) should be considered as differential diagnoses.

Arterial thromboembolism: Treatment

Treatment should he directed at alleviating signs associated with the thrombus as well as the underlying cardiac disorder responsible for its formation. Aspirin (25 mg kg-1 body weight per os every 72 h) should be given to inhibit platelet function. One study showed that the administration of aspirin resulted in significant preservation of collateral blood supply in eats after experimental induction of iliac thrombosis and a shortening of the recovery period. However, there is evidence to suggest that aspirin is not effective in preventing further embolic episodes. The use of acepromazine (0,2-0.4 mg kg-1 bodyweight subcutaneously three times daily) has been advocated for its vasodilator properties. Heparin may be given to prevent further activation of the coagulation process (an initial intravenous dose of 1000 USP followed 3 h later by 50 USP units kg-1 body weight subcutancously and thereafter 50 USP units kg-1 bodyweight every 6-8 b). Regular daily monitoring of activated partial thromboplastin lime (APTT) is advised so that the APTT is not prolonged by more than 1.5-2,0 times the preheparin baseline values. Morphine (0.1 mg kg-1 bodyweight) can be given as an analgesic for the first 24-48 h.

The use of the serotonin antagonist, cyproheptadine, and thrombolvtic agents such as streptokinase, urokinase and tissue plasminogen activator (t-PA) have yet to be fully evaluated and to date the results have been equivocal.

Prognosis

The prognosis is at best guarded. Many animals fail to respond to medical management or succumb to the underlying cardiomyopathy. Recurrence is common. Spontaneous recanalization of the clot may occur with or without drug therapy after 2-4 days. Many cats are left with signs of residual peripheral nerve damage. Full recovery may take up to 4-6 weeks.

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Veterinary Medicine

Dirofilariasis

Canine heart worm disease caused by Dirofilaria immitis is endemic in most temperate and tropical coastal zones of the world (United States. Japan and Australia especially). Heartworm disease is occasionally diagnosed in imported dogs in the United Kingdom. Affected animals are often between 4 and 7 years of age although the condition has been diagnosed in animals less than one year of age.

Life cycle of Dirofilaria immitis

When a mosquito bites an infected dog circulating microfilaria (first stage larvae) are ingested and develop into third stage (L3) larvae which migrate to the mouth parts of the mosquito. The third larval stage of the heartworm (Dirofilaria immitis) stage enters the subcutaneous tissues of the host via a bite from an infected mosquito. Young adult worms (L5 stage) reach the right side of the heart by 90-100 days postinfection. There is a prepatent time of approximately 6 months before microfilaria appear in the circulation. Occult infections occur where there is an absence of circulating microfilaria.

Pathophysiology of heartworm disease

Adult worms live most commonly in the right ventricle, main pulmonary artery and parenchymal pulmonary arteries. As the number of heart-worms increases they enter the right atrium and eventually migrate into the caudal vena cava. Large numbers of worms may obstruct the caudal vena cava and flow of blood to the right atrium (vena caval syndrome).

Adult worms initiate a parasite-host reaction which damages the pulmonary artery endothelium. Histologically this reaction is characterized by the proliferation of smooth muscle cells on the endothelial surface of the vessels. Circulating antibodies trap the microfilaria within the pulmonary arteries which results in pulmonary infarction and areas of consolidation around the affected vessels. Alveolar hypoxia increases pulmonary vascular resistance and leads to pulmonary hypertension. Pulmonary hypertension results in increased right ventricular afterload, right ventricular hypertrophy and eventually signs of right-sided heart failure (cor pulmonale).

Clinical signs

The clinical signs of heartworm disease, once apparent, are usually severe and progress rapidly. Damage to the pulmonary arteries results in coughing, haemoptysis, dyspnoea and decreased exercise tolerance. There is a rapid loss of body condition and pulmonary hypertension leads to right-sided heart failure. Tricuspid valve murmurs may be heard due to mechanical interference with valvular function by the adult worms.

Some infected dogs show few if any clinical signs. Those with occult heartworm disease develop an allergic pneumonitis characterized by severe coughing and dyspnoea. Two conditions which may have an immune-mediated pathogenesis, eosinophilic granulomatosis and pulmonary infiltrates with eosinophilia (eosinophilic pneumonia), may also occur in association with heart-worm disease. Severe pulmonary artery disease may result in thromboembolic complications and thrombocytopenia especially after adulticide therapy.

Haemolysis and haemoglobinuria may occur when a large number of worms obstruct the caudal vena cava and result in fragmentation of red cells. Dogs with the caval syndrome become severely dyspnoeic and show signs of acute hypotension (tachycardia, pale mucous membranes and prolonged capillary refill time).

Electro cartography

Electrocardiographs signs of right ventricular enlargement may be evident especially in dogs showing signs of right-sided heart failure.

Radiographic findings

Radiographic changes develop early during the course of heartworm infection. Typical abnormalities include right ventricular enlargement and a bulging pulmonary artery segement with enlarged lobar pulmonary arteries. As the disease progresses the peripheral pulmonary arteries become truncated and tortuous especially in the caudal lung lobes. Patchy alveolar densities may be apparent especially after adulticide therapy.

Clinicopathological findings

Eosinophilia often accompanied by basophilia are the most consistent haematological abnormalities, occurring once die young adult worms enter the circulation. A mild regenerative anaemia may be present and neutrophilia may occur following aduhicide treatment. Platelet numbers are often reduced as a result of increased consumption in response to endothelial damage. Liver enzymes may be increased especially if signs of right-sided cardiac failure are present; total plasma proteins may also be increased due to an increase in the globulin fraction. Proteinuria occurs in 20-30% of cases; some animals develop a glomerulonephropathy and nephrotic syndrome, and become hypoalbuminaemic.

Diagnosis of Dirofilariasis

The presence of microfilaria on a peripheral blood film implies the presence of adult worms. Dirofilaria immitis microfilaria should be differentiated from those of Dipetalonema reconditum and other Dipetalonema species which cause asymptomatic infections in dogs. This can be done by examining the acid phosphatase staining pattern of filter-treated micro-filariae. The blood of young dogs from endemic areas should be screened annually for the presence of microfilaria using a Knott’s test. With occult infections, no circulating microfilaria are present and diagnosis is dependent on the detection of appropriate radiographic abnormalities and the results of other serodiagnostic tests.

An indirect fluorescent antibodv test detecting antibodies to microfilarial antigens is useful in the diagnosis of occult heartworm disease. An ELISA test for detecting antibodies against adult worms has proved to be less satisfactory because of the high incidence of false positive results, although a negative ELISA result can be regarded as reliable evidence that occult heart-worm disease is not present. More recently, ELISA tests using monoclonal antibodies against circulating adult antigens have been developed which appear to be more sensitive and specific than tests which detect adult antibodies.

Dirofilariasis: Treatment

Adulticide therapy

Thiacetarsamide (22 mg kg-1 body weight intravenously twice daily for two days) eliminates a high percentage of the adult heart worms (young female heart worms are often resistant). The second dose should be given not more than 10 hours after the first. Treatment with thiacetarsamide should be delayed in dogs with radiographic signs of severe pulmonary artery disease since such animals are at risk from developing thromboembolic complications and thrombocytopenia post-treatment. Toxic reactions to thiacetarsamide occasionally occur; these include anorexia, vomiting, depression, fever, diarrhoea and the presence of tubular casts in the urine. Adulticide treatment is usually followed 4-6 weeks later by the administration of a microfilaricide. The benefits of giving a microfilaricide three weeks before treatment with thiacetarsamide are questionable.

Levamisole has been used as an alternative adulticide drug but is less effective than thiacetarsamide. It is more effective as a microfilaricidal drug but toxic side effects (vomiting and CNS signs) are common.

The prophylactic use of aspirin to combat the potential thromboembolic complications has been questioned. Recent studies have shown that even doses of aspirin greater than 50 mg kg-1 in some dogs will not prevent thromboembolism or imimal hyperplasia associated with heart worm emboli.

Corticosteroids are indicated if there is evidence of an eosinophilic pulmonary infiltrate. Heparin has been recommended for dogs showing signs of chronic or low-grade disseminated intravascular coagulation (DIC).

Microfilaricide treatment

Levamisole, milbemycin and ivermectin are available for use as microfilaricides (the last two can also be used prophylactically). The American Heartworm Society currently recommends that cither ivermectin (50 μg kg-1) or milbemycin (500 μg kg-1) be given 3-4 weeks after treatment with adulticide. Treatment of dogs with large numbers of microfilaria may lead to circulatory collapse due to rapid death of the microfilaria. Dogs should therefore be observed for 6-8 h after treatment. The use of ivermectin and milbemycin in collies and collie cross breeds has been associated with anaphylactic reactions and, in some cases, death; although both the microfilaricidal and the preventative doses of these drugs are reportedly safe in susceptible collies other drugs, for example levamisole (10 mg kg-1 day-1 for 7 days) have been recommended for this breed.

Prevention of heartworm disease

Chemoprophylaxis should be initiated 2-3 weeks after administration of a microfilaricide providing no microfilariae are detected in the blood; if microfilariae are still present microfilaricidal treatment should be repeated). In endemic areas, either ivermectin (6-12 μg kg-1) or milbemycin (500-999 μg kg-1) can be administered once a month. Young pups can be treated prophylactically from 6-8 weeks of age onwards. Although both drugs can be safely given to dogs which may already have circulating microfilariae, they only kill D. immitis larvae during the first six weeks of their development. Both drugs are also known to induce sterility in adult worms there-fore dogs greater than 6 months of age on monthly preventative treatment should be tested for antigen to detect occult infections which may develop within 6 months of starting monthly macrolide administration.

Categories
Veterinary Medicine

Cor pulmonale

Cor pulmonale is the term used to describe the alterations in the structure or function of the right ventricle which may be induced by pulmonary hypertension secondary to primary lung disease.

Pathophystology of cor pulmonale

Cor pulmonale may be acute or chronic. Alveolar hypoxia and hypoxaemia, respiratory acidosis and hypercapnoea combine to increase pulmonary vascular resistance. Pulmonary hypertension results in acute or chronic right ventricular pressure overload, right ventricular hypertrophy and eventually signs of right-sided failure.

Acute cor pulmonale caused by pulmonary thromboembolism or heartworm disease is of ten fatal and in most cases may not be diagnosed. Pulmonary thromboembolism can occur as a complication of chronic renal disease (especially glomerulo-nephropathy), hyperadrenocorticism, immune-mediated haemolytic anaemia and pancreatitis.

Chronic cor pulmonale may occur as a sequel to chronic obstructive pulmonary disease. It has been associated with chronic bronchitis, bronchiectasis, pulmonary fibrosis, infiltrative lung disease (for example neoplasia), chronic partial upper airway obstruction due to collapsing trachea, laryngeal paralysis or elongation of the soft palate, and heartworm disease.

Clinical signs of cor pulmonale

Animals with acute cor pulmonale due to pulmonary thrombosis present with severe dyspnoea and are often cyanotic. The mortality rate is high. The clinical signs of chronic cor pulmonale depend on the nature and severity of the underlying respiratory disorder. A chronic cough and / or wheezing is common in dogs with chronic bronchitis, bronchiectasis and collapsing trachea; dogs with chronic partial upper airway obstruction due to an elongated soft palate or laryngeal dysfunction may become progressively dyspnoeic with signs of inspiratory stridor / stertor. Failure to treat the underlying problem may lead to signs of right-sided congestive heart failure.

Electrocardiography

Pulmonary hypertension and resultant right ventricular hypertrophy may result in tall P waves (right atrial enlargement) and deep Q or S waves in leads I. II. III and aVF (right ventricular enlargement). The mean electrical axis may shift to the right and myocardial hypoxia may result in ST segment depression.

Radiographic findings

Acute pulmonary thromboembolism results in pulmonary hypoperfusion and lobar hyperlucency. Pulmonary vessels may appear truncated especially towards the periphery. A minimal amount of pleural fluid may be present. Right ventricular enlargement is a feature of chronic cor pulmonale and many animals will show concurrent radiographic changes consistent with chronic lung disease, for example a diffuse bronchial and / or interstitial pattern or bronchiectasis.

Cfinicopathological findings

Blood gas analysis

Hypoxia (PaO2 <80 mm Hg), hypercapnoea (PaCO2 >40 mm Hg) and acidosis (pH <7.4) reflect the severity of the underlying pulmonary pathology. Chronic hypoxia occasionally results in secondary polycythaemia. Animals with acute pulmonary thromboembolism may become thrombocytopenic and show other laboratory evidence of disseminated intravascular coagulation. Pulmonary hypertension and right ventricular pressure overload result in an increase in central venous pressure.

In addition to the above, diagnostic investigations such as bronchoscopy and tracheal or bronchoalveolar lavage should be performed where appropriate to establish the nature of the underlying respiratory disorder responsible for the cardiac changes.

Cor pulmonale: Treatment

Treatment of the underlying pulmonary condition should be instituted as quickly as possible. Acute pulmonary thromboembolism should be treated with cage rest, oxygen and antithrombotic drugs such as heparin and aspirin. The prognosis is generally poor if signs of right-sided heart failure are present.

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Veterinary Procedures

Blood Collection Techniques

In most instances, a 3- to 5-mL sample of anticoagulated whole blood is adequate for routine hematology; some laboratories will accept as little as 1 mL. For routine biochemical analyses, the volume of serum requested can vary from 1 to 2 mL, depending on the number and type of tests requested. Plan ahead which samples are required to prevent the need for further venipuncture at a later time. In small dogs and cats, using the jugular veins facilitates collection of an adequate volume of blood. If smaller samples are required, the cephalic, lateral saphenous, or medial saphenous vein can be used for sample collection. Do not use the jugular vein if a coagulopathy is suspected, as hemorrhage may be difficult to control after venipuncture.

Patient Preparation

For successful venipuncture, proper restraint of the animal is important. Details for the proper restraint for various venipuncture locations are discussed with each specific topic throughout this text. The patient must remain comfortable yet relatively motionless to avoid iatrogenic vessel laceration. Stretch the skin tightly over the selected vessel without causing vascular occlusion to help anchor the vessel in place during penetration by the needle.

Technique

The specific venipuncture will vary somewhat depending on the specific vein selected. The following sections describe venipuncture technique for each of four commonly accessed veins: the cephalic vein, jugular vein, lateral saphenous vein, and medial saphenous vein.

Cephalic Venipuncture

To restrain a dog or cat for venipuncture of the cephalic vein, place the dog or cat on the table, sitting or in sternal recumbency. If the right vein is to be tapped or catheterized, the assistant should stand on the left side of the animal and place the left arm or hand under the animal’s chin to immobilize the head and neck. The assistant should reach across the animal and grasp the leg just behind and distal to the right elbow joint. The assistant should use the thumb to occlude and rotate the cephalic vein laterally while the palm of the hand holds the elbow in an immobilized and extended position. Make sure that the animal stays on the table if struggling occurs. The person performing the venipuncture then grasps the leg at the metacarpal region and begins the venipuncture on the medial aspect of the leg, just adjacent to the cephalic vein proximal to the carpus.

Jugular Venipuncture

For a jugular venipuncture in the dog, place the patient in sternal recumbency, with the hands of the assistant placed around the patients muzzle to extend the neck and nose dorsally toward the ceiling. In short-coated dogs, the jugular vein usually can be seen coursing from the ramus of the mandible to the thoracic inlet in the jugular furrow. The vessel may be more difficult to visualize in dogs with long hair coats or if excessive subcutaneous fat or skin is present. The person performing the venipuncture should place the thumb of the nondominant hand across the jugular vein in the thoracic inlet or proximal to the thoracic inlet to occlude venous drainage from the vessel and allow it to fill. With the dominant hand, the person performing the venipuncture should insert the needle and syringe or Vacutainer (BD, Franklin Lakes, New Jersey) into the vessel at a 15- to 30-degree angle to perform the venipuncture.

For smaller and very large animals, the jugular vein also can be tapped by placing the patient in lateral recumbency. The assistant should pull the animal’s front legs caudally and extend the head and neck so that the jugular vein can be visualized. The venipuncture then can be performed as previously described. A jugular venipuncture is contraindicated in patients with thrombocytopenia or vitamin K-antagonist rodenticide intoxication.

Place cats in sternal recumbency. The assistant should stand behind the patient so that the patient cannot back away from the needle during the venipuncture. The assistant should extend the cat’s head and neck dorsally while restraining the cat’s front legs with the other hand. The cat’s fur can be clipped or moistened with isopropyl alcohol to aid in visualization of the jugular vein as it stands up in the jugular furrow. The person performing the venipuncture should occlude the vessel at the thoracic inlet and insert the needle or Vacutainer apparatus into the vessel as previously described to withdraw the blood sample. Alternately, place the cat in lateral recumbency as described in the previous paragraph.

Lateral Saphenous Venipuncture

To perform a lateral saphenous venipuncture, place the patient in lateral recumbency. The lateral saphenous vein can be visualized on the lateral portion of the stifle, just proximal to the tarsus. The assistant should extend the hindlimb and occlude the lateral saphenous vein just proximal and caudal to the tarsus. The person performing the venipuncture should grasp the distal portion of the patient’s limb with the nondominant hand and insert the needle or Vacutainer apparatus with the dominant hand to withdraw the blood sample.

Medial Saphenous Venipuncture

To perform a medial saphenous venipuncture, place the patient in lateral recumbency. Move the top hindlimb cranially or caudally to allow visualization of the medial saphenous vein on the medial aspect of the tibia and fibula. The assistant should scruff the patient, if the patient is small, or should place the forearm over the patient’s neck to prevent the patient from getting up during the procedure. With the other hand, the assistant should occlude the medial saphenous vein in the inguinal region. The person performing the medial saphenous venipuncture should grasp the paw or hock of the limb and pull the skin taut to prevent the vessel from rolling away from the needle. The fur may be clipped or moistened with isopropyl alcohol to aid in visualization of the vessel. The needle or Vacutainer apparatus can be inserted into the vessel at a 15- to 30-degree angle to withdraw the blood sample.

Special Considerations

Incorrect proportions of blood to anticoagulant may result in water shifts between plasma and red blood cells (RBCs). Such shifts may alter the packed cell volume (PCV), especially when small amounts of blood are added to tubes prepared with volumes of anticoagulant sufficient for much larger volumes of blood. Erroneous laboratory results also may be obtained when small volumes of blood are placed in a relatively large container. Evaporation of plasma water and adherence of the cells to the surface of the container can produce arti-factual changes in hematologic results.

Refrigerate liquid blood mixed with anticoagulant after collection if the sample is to be held before being transported to a laboratory. White blood cell (WBC) and RBC counts, PCV, and hemoglobin level can be measured within 24 hours of sample collection. Platelet counts, however, should be done within 1 hour of collection. Dried, unfixed blood smears can be stained with most conventional stains 24 to 48 hours after being made. If a considerable delay is anticipated between the time that the blood smear is made and the staining process, the blood smear should be fixed by immersion in absolute methanol for at least 5 minutes. Blood smears fixed by this method are stable indefinitely.

Never place unfixed blood smears in a refrigerator because condensation forming after the smear is removed from the refrigerator will ruin the blood smear and make it unusable for cytologic evaluation. Take care to leave unfixed blood smears face down on a countertop or in a closed box. Special stains, such as peroxidase, may require fresh blood films.

Routine Hematologic Testing

The anticoagulant of choice for hematologic testing is EDTA. Heparin is especially to be avoided if blood films are to be made from blood mixed with anticoagulant because contact with whole blood will distort the morphology of cells significantly. Heparin is acceptable for most procedures requiring blood plasma. The anticoagulant effect of heparin is transitory. Specimens still may clot after 2 to 3 days.

Make blood films immediately after collection because cell morphology rapidly deteriorates after sample collection. Although blood films can be made after introducing blood to EDTA, a better practice is to make blood smears (films) immediately from the collection needle before the blood comes in contact with any anticoagulant. Never use blood exposed to heparin to make blood smears.

Incorrect proportions of blood to anticoagulant may result in water shifts between plasma and RBCs. Such shifts may alter the PCV, especially when small amounts of blood are added to tubes prepared with volumes of anticoagulant sufficient for much larger volumes of blood. Erroneous laboratory results also may be obtained when small volumes of blood are placed in a relatively large container. Evaporation of plasma water and adherence of the cells to the surface of the container can produce artifactual changes in hematologic results.

Refrigerate liquid blood mixed with anticoagulant after collection if there is a delay in making the laboratory determinations. WBC and RBC counts, PCV, and hemoglobin level can be measured within 24 hours of sample collection. Platelet counts, however, should be done within 1 hour of collection. Dried, unfixed blood smears can be stained with most conventional stains 24 to 48 hours after being made. If a considerable delay is anticipated between the time that the blood smear is made and the staining process, the blood smear should be fixed by immersion in absolute methanol for at least 5 minutes. Blood smears fixed by this method are stable indefinitely. Neverplace unfixed blood smears in a refrigerator because condensation forming after the smear is removed from the refrigerator will ruin the blood smear and make it unusable for cytologic evaluation. Take care to leave unfixed blood smears face down on a countertop or in a closed box. Special stains, such as peroxidase, may require fresh blood films.

Routine Biochemistry Testing

Patient Preparation

Prepare the selected vein as described earlier.

Technique

Most clinical chemistry procedures are performed on serum. The serum is obtained by collecting blood without any anticoagulant and allowing the blood to clot in a clean, dry tube. Separate serum from cells within 45 minutes of sample collection (venipuncture). Special vacuum vials are available that produce a gel barrier between the clot and the serum (serum separator tubes) which avoid the need to draw off the serum into a separate vial. Clotting of the blood and retraction of the clot occur best and maximum yields of serum are obtained at room or body temperature. Refrigeration of the sample delays clot retraction. Some samples clot and retract faster than others.

Special Considerations

If a serum separator tube is not used, it is recommended to free the clot from the walls of the container by rimming with an applicator stick. After the clot is freed, allow clot retraction to occur, and then centrifuge and draw off the clear supernatant serum using a pipette or suction bulb. Allow whole blood samples to completely clot before attempting to remove serum. Failing to do so may result in a mixture of plasma and serum in the submitted sample. Serum yield is usually one third of the whole blood volume. Patients that are hypovolemic or dehydrated can have a significantly lower serum yield.

Many clinical chemistry procedures can be performed on plasma and on serum. The advantage of using plasma is that separation of cells can be accomplished immediately after centrifugation or sedimentation, without the need to wait for clot formation and retraction. The disadvantage of plasma is that the presence of the anticoagulant interferes with many of the chemistry assay procedures. Plasma is less clear than serum, which may be an additional disadvantage for colorimetric assays. Plasma and serum are virtually identical in chemical composition except that plasma has fibrinogen and the anticoagulant. For many procedures in which plasma or whole blood is to be used, heparin is the anticoagulant of choice. Heparinized blood is the only acceptable specimen for blood pH and blood gas analyses. Although blood containing EDTA is acceptable for certain chemical procedures, it cannot be used for determination of plasma electrolytes because it contributes to and sequesters them from the specimen. In addition, EDTA can interfere with alkaline phosphatase levels, decrease total carbon dioxide, and elevate blood nonprotein nitrogen.

Refer to the Tube Selection Guide in Section 5 to assure use the proper collection tube is used for the appropriate test requested.

Separate serum or plasma and remove it from the cells as soon as possible after blood is collected, because many of the constituents of plasma exist in higher concentrations in RBCs. With time, these substances leak into the plasma and cause falsely elevated values (positive interference) and falsely lower values (negative interference) (Table Examples of Positive and Negative Interference on Biochemistry Analytes Induced by Sample Hemolysis). Under no circumstances should whole blood be sent via the mail; serum derived from such specimens usually is hemolyzed, and results are often inaccurate. Separate serum and transfer it to a clean, dry tube for shipment.

TABLE Examples of Positive and Negative Interference on Biochemistry Analytes Induced by Sample Hemolysis

Analyte Effect of Hemolysis*
Alanine transaminase Minimal effect
Alkaline phosphatase Increased
Bilirubin Increased
Chloride Decreased
Creatinine Increased
Inorganic phosphate Increased
Lipase Decreased
pH Decreased
Potassium No detectable effect
Total calcium Increased
Total protein Increased
Urea nitrogen Increased

*Type and degree of interference vary among different testing modalities unique to individual laboratories or in-hospital biochemistry analyzers.

Categories
Diseases

Therapy Of Thromboembolic Disease

The management of primary diseases resulting in the development of thromboembolism is discussed in related posts throughout this textbook. Therapy of thromboembolism should be directed toward the underlying disorder whenever possible. Therapeutic strategies for managing thromboembolism include short-term systemic anticoagulation and fibrinolysis followed by long-term antiplatelet or anticoagulant therapy to reduce the risk of rethrombosis.

Supportive Care

General patient care is critical for successful management of thrombosis. Analgesic agents should be considered for acute pain management. Fluid therapy should be administered when indicated to correct acid-base abnormalities and dehydration. Dextrose-containing fluids should be avoided whenever possible because they may cause endothelial damage, further promoting thrombosis. A risk of volume overload exists with heart failure or pulmonary hypertension and fluid therapy must be carefully monitored. Strict cage rest and oxygen therapy are indicated in cases of pulmonary thromboembolism or thrombosis associated with congestive heart failure (CHF).

Acute Anticoagulation

Heparin is the mainstay of acute anticoagulation. Anticoagulants prevent additional clots from forming but do not dissolve clots (see thrombolysis). Coumadin therapy for the long-term control of thrombosis is initiated after adequate hepariniza-tion has been achieved.

Heparin functions as a cofactor with antithrombin III, and together this complex exerts its effect by neutralizing factor X and thrombin. Heparin is inactivated by gastrointestinal (GI) enzymes when given orally and therefore must be administered by injection. Heparin is administered to prolong the baseline activated partial thromboplastin time (aPTT) to 1.5 to 3.0 times the baseline value. Prolongation of the aPTT or activated coagulation time (ACT) does not correlate well with heparin levels in cats and dogs, and measurement of plasma heparin levels may be more useful in monitoring heparin therapy. Although many different heparin doses have been advocated, little clinical data exist concerning efficacy. Doses of heparin required to achieve adequate heparin levels in cats with thromboembolism ranged from 175 U/kg every 6 hours to 475 U/kg every 8 hours, subcutaneously. In normal dogs the dose of heparin required to achieve adequate heparin concentrations was 250 U/kg every 6 hours, subcutaneously. The most common side effect of heparin therapy is hemorrhage. In the event of severe hemorrhage, heparin can be neutralized by protamine sulfate administration.

Low molecular weight (LMW) heparin is being increasingly used. Its anticoagulant effect is limited to blocking the activity of factor X. Because LMW heparin has a lower antithrombin effect than unfractionated heparin, LMW heparin does not markedly influence the PT or aPlT. Measurement of factor X activity has been used to assess the effect of LMW heparin. One advantage of LMW heparin is that it has a lower risk of hemorrhage than conventional hep-arin therapy. The optimal dose of LMW heparin in dogs and cats with thromboembolic disease remains to be determined.

Chronic Anticoagulation

Warfarin (Coumadin) is a vitamin K antagonist inhibiting the synthesis of vitamin K-dependent clotting proteins (prothrom-bin and factors VII, IX and X). In addition, warfarin reduces efficacy of the vitamin K-dependent regulatory proteins C and S. Proteins C and S are anticoagulant factors, and their function is the first to be inhibited by warfarin administration. Therefore heparin and warfarin administration are generally overlapped for 2 to 4 days to prevent a transient hypercoagulable state. Some animals appear to do well with just warfarin. Starting doses for warfarin are 0.25 to 0.5 mg every 24 hours in the cat and 0.1 to 0.2 mg/kg every 24 hours in the dog. Due to the high individual patient variability, close monitoring of PT is essential. Early recommendations were to maintain PT 1.5 times the baseline value, and more recent recommendations suggest attaining an international normalized ratio (INR) of 2:3. INR is calculated by the formula (patient PT/control PT). The ISI is a value specific to the tissue thromboplastin that is used in measuring the PT Coumadin is continued on a long-term basis to prevent recurrent TE. Studies documenting the optimal dose, efficacy, and duration of Coumadin therapy for specific thromboembolic diseases in dogs and cats are unknown.

The use of Coumadin is not without risks. The major risk is fatal hemorrhage, which occurs acutely and unexpectedly. Ideally, pets maintained on Coumadin should live indoors and be well supervised to prevent trauma and to monitor for hemorrhage. Periodic measurement of the PT should be done to ensure adequate dosing. Coumadin interacts with many drugs. The addition of medications to the treatment regimen of a pet on Coumadin should be done cautiously because certain drugs will raise the activity of Coumadin and predispose patients to bleeding. Some of these drugs are phenylbutazone, metronidazole, trimethoprim sulfa, and second- and third-generation cephalosporins. Barbiturates will decrease Coumadin anticoagulant effect. If bleeding complications occur, warfarin therapy is discontinued and administration of vitamin K is recommended.

Antiplatelet Therapy

Antiplatelet drugs have been advocated for long-term management to prevent rethrombosis. These drugs inhibit platelet aggregation and adhesion, preventing the formation of the hemostatic platelet plug. Aspirin inhibits cyclooxygenase, leading to decreased thromboxane A2 synthesis. This renders platelets nonfunctional by preventing their aggregation. Cats lack the enzyme needed to metabolize aspirin (glucuronyl transferase), making them sensitive to aspirin-induced platelet dysfunction. Doses of 0.5 mg/kg every 12 hours in the dog and 25 mg/kg twice weekly in the cat may decrease platelet aggregation. However, rethrombosis generally occurs despite aspirin therapy, although it is not known whether aspirin delays recrudescence. Additional antiplatelet drugs include dipyridamole and ticlopidine. Dipyridamole is thought to inhibit platelet aggregation by inhibition of platelet phospho-diesterase, leading to increased levels of cyclic adenosine monophosphate (cAMP) within platelets. Ticlopidine impairs fibrinogen binding and inhibits platelet aggregation induced by ADP and collagen. The use of these newer compounds has been limited thus far in veterinary medicine.

Thrombolysis

Thrombolytic agents such as streptokinase, urokinase, and tissue plasminogen activator (tPA) are potent activators of fib-rinolysis. These agents have been used with variable and often limited success in veterinary medicine.

Streptokinase binds plasminogen, and the complex transforms other plasminogen molecules into plasm in. Plasmin then binds to fibrin and causes thrombolysis. Streptokinase binds both free and clot-associated plasminogen. It also degrades factors V, VIII, and prothrombin, resulting in a massive systemic coagulation defect.

Streptokinase has been used to treat aortic thromboembolism (ATE) in cats with varying degrees of success. In one study of 46 cats, 15 were discharged from the hospital after streptokinase therapy with a median survival of 51 days. Reperfusion injury occurred in approximately 35% after thrombolysis, with streptokinase often resulting in fatal hyperkalemia and metabolic acidosis- Eleven of the cats developed clinical hemorrhage after streptokinase therapy. In three cats, hemorrhage was significant enough to require transfusion. Others reported conservative management (treatment of heart failure plus Coumadin or aspirin) of thromboembolism with a hospital discharge rate of 28%, which was similar to cats treated with streptokinase. One recommended dose of streptokinase for dogs and cats with thromboembolism is 90,000 U, intravenously administered over 20 to 30 minutes, followed by a maintenance infusion of 45,000 U for 7 to 12 hours. Infusions may be repeated over a total of 3 days.

Recombinant DNA technology produces t-PA, a serine protease. A complex forms between t-PA and fibrin, and that complex preferentially activates thrombus-associated plasminogen-resulting in rapid fibrinolysis. Life-threatening hemorrhage is the number one side effect. The half-life of t-PA in dogs is 2 to 3 minutes; consequendy, if bleeding occurs, stopping the infusion will result in the drug clearance from the system in 5 to 10 minutes. Because t-PA causes rapid thrombolysis, the risk of reperfusion syndrome and lethal hyperkalemia is substantial. In one report, 50% of cats with thromboembolism died acutely during t-PA therapy, with death attributed to hyperkalemia, severe anemia, and renal hemorrhage.

Categories
Drugs

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based (Abelcet, Fungizone)

Antifungal

Highlights Of Prescribing Information

Systemic antifungal used for serious mycotic infections

Must be administered IV

Nephrotoxicity is biggest concern, particularly with the deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive

Renal function monitoring essential

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based interactions

What Is Amphotericin B Desoxycholate, Amphotericin B Lipid-Based Used For?

Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

The liposomal form of amphotericin B can be used to treat Leishmaniasis.

Pharmacology / Actions

Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out.” Because bacteria and rickettsia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp.

It has been reported that amphotericin B has immunoadjuvant properties but further work is necessary to confirm the clinical significance of this effect.

Pharmacokinetics

Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form.

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

Before you take Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

Contraindications / Precautions / Warnings

Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but it should be used cautiously with adequate monitoring.

Adverse Effects

Amphotericin B is notorious for its nephrotoxic effects; most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in patients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require several months to do so.

Newer forms of lipid-complexed and liposome-encapsulated amphotericin B significantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that amphotericin B lipid complex was 8-10 times less nephrotoxic than the conventional form.

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recommend stopping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dL, serum creatinine >3 mg/dL or if other clinical signs of systemic toxicity develop such as serious depression or vomiting.

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12.5 grams or 0.5-1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 mL/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “… helpful in averting renal insufficiency….”

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse.

Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hypokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regenerative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been reported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels.

Reproductive / Nursing Safety

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Prohahly safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women.)

Overdosage / Acute Toxicity

No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe minimized by administering fluids and mannitol as outlined above in the Adverse Effects section.

How to use Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

All dosages are for amphotericin B desoxycholate (regular amphotericin B) unless specifically noted for the lipid-based products.

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

A published study () demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin BIV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 mL of D5W over 3 minutes.

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for dogs:

For treatment of susceptible systemic fungal infections:

a) Two regimens can be used; after diluting vial (as outlined below in preparation of solution section), either:

1) Rapid-Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given.

2) Slow IV Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 250-500 mL of D5W. Place indwelling catheter in peripheral vein and give total volume over 4-6 hours. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

b) In dehydrated, sodium-depleted animals, must rehydrate before administration. Dosage is 0.5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 mL of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 mL or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer every other day if BUN remains below 50 mg/dl. If BUN exceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8 -10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, aspergillosis and other fungal diseases require a greater cumulative dosage. ()

c) For treating systemic mycoses using the lipid-based products: AmBisome, Amphocil or Abelcet Give test dose of 0.5 mg/ kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more resistant filamentous fungal infections (e.g., pythiosis) use the higher dose 2-2.5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

e) For systemic mycoses using amphotericin B lipid complex (Abelcet): Dilute in 5% dextrose to a final concentration of 1 mg/mL and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B 0.5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5-5 mg/kg PO once daily. If CNS/ocular involvement use ketoconazole at 20-40 mg/kg PO divided twice daily ()

c) For severe cases, using amphotericin B lipid complex (Abelcet): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg ()

For cryptococcosis (see general dosage guidelines above):

a) Amphotericin B 0.5 – 0.8 mg/kg SC 2 – 3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B 0.15 – 0.5 mg/kg IV 3 times a week with ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

b) As an alternative to ketoconazole treatment: 0.5 mg/kg IV given over 6-8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7.5-8.5 mg/kg cumulative dose is achieved ()

For Leishmaniasis:

a) Using the liposomal form of Amphotericin B: 3-3.3 mg/kg IV 3 times weekly for 3-5 treatments)

b) Using AmBisome (lipid-based product): Give initial test dose of 0.5 mg/kg, then 3-3.3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. ()

For gastrointestinal pythiosis:

a) Resect lesions that are surgically removable to obtain 5 – 6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for cats:

For treatment of susceptible systemic fungal infections: a) Rapid-Infusion Technique: After diluting vial (as outlined below in preparation of solution section), dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.25 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

For cryptococcosis (see general dosage guidelines above):

a) As an alternative therapy to ketoconazole: Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with flucytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989)

b) Amphotericin B 0.15-0.4 mg/kg IV 3 times a week with flucytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily ()

c) Amphotericin B 0.5-0.8 mg/kg SC 2-3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN increases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of duration. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0.5 mg/ kg of amphotericin B. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5 – 5 mg/kg PO once daily. If CNS/ocular involvement, use ketoconazole at 20-40 mg/kg PO divided twice daily. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for rabbits, rodents, and small mammals:

a) Rabbits: 1 mg/kg/day IV ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for horses:

For treatment of susceptible systemic fungal infections:

a) For fungal pneumonia: Day 1: 0.3 mg/kg IV; Day 2: 0.4 mg/kg IV; Day 3: 0.6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6.75 mg/kg has been administered ()

b) For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0.3 mg/kg IV; Day 2: 0.45 mg/kg IV; Day 3: 0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. ()

For intrauterine infusion: 200-250 mg. Little science is available for recommending doses, volume infused, frequency, diluents, etc. Most intrauterine treatments are commonly performed every day or every other day for 3-7 days. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for Llamas:

For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1.5 mL of B-Complex and 20 mEq of KC1 added. Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coccidioidomycosis). ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for birds:

For treatment of susceptible systemic fungal infections:

a) For raptors and psittacines with aspergillosis: 1.5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/mL of saline) for 15 minutes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. ()

b) 1.5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0.3-1 mg/mL nebulized for 15 minutes 2-4 times daily ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for reptiles:

For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intratracheally once daily for 14-28 treatments ()

Client Information

■ Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy

■ The costs associated with therapy

Chemistry / Synonyms

A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent.

Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B liposomal (ABL, L-AMB, Ambisome).

Amphotericin B may also be known as: amphotericin; amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available.

Storage / Stability / Compatibility

Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives — see directions for preparation in the Dosage Form section below).

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, Ds-lactated Ringer’s, amino acids 4.25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCL, cimetidine HCL, diphenhydramine HCL, dopamine HCL, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCL, metaraminol bitartrate, methyldopate HCL, nitrofurantoin sodium, oxytetracycline HCL, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCL, and verapamil HCL. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin (Gensia Sicor); Fungizone Intravenous (Apothecon); generic (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 mL of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/mL colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/mL with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 mL (as lipid complex) in 10 mL & 20 mL vials with 5 micron filter needles: Abelcet (Enzon); (Rx)

Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 mL vials; 100 mg (as cholesteryl) in 50 mL vials; Amphotec (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; AmBisome (Fujisawa; (Rx)

Amphotericin B is also available in topical formulations: Fungizone (Apothecon); (Rx)

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

Categories
Diseases

Canine Heartworm Disease: Ancillary Therapy

Corticosteroids

The anti-inflammatory and immunosuppressive effects inherent to corticosteroids are useful for treatment of some aspects of HWD. Prednisone, the steroid most often advocated, reduces pulmonary arteritis but actually worsens the proliferative vascular lesions of HWD, diminishes pulmonary arterial flow, and reduces the effectiveness of thiacetarsemide. For these reasons, corticosteroids are indicated in heartworm disease only in the face of pulmonary parenchymal complications (eosinophilic pneumonitis, eosinophilic granulomas, and PTE), to treat or prevent adverse reactions to microfilaricides, and possibly to minimize tissue reaction to melarsomine. For allergic pneumonias, prednisone (1 mg/kg/day) is administered for 3 to 5 days and discontinued or tapered as indicated. The response is generally favorable. Prednisone has also been advocated, along with cage rest, for the management of postadulticidal thromboembolization at 1 to 2 mg/kg per day, continued until radiographic and clinical improvement is noted. Because of the potential for steroid-induced fluid retention, such therapy should be used cautiously in the face of heart failure. In addition, caution is warranted because early studies demonstrated that postadulticidal corticosteroid therapy reduced pulmonary blood flow and worsened intimal disease in a model of HWI; corticosteroids are also procoagulant As mentioned with adulucidal (previously discussed) and microfilaricidal (discussed following) therapies, corticosteroids may be used to minimize potential adverse reactions to melarsomine and to macrolides given to rapidly kill microfilariae.

Aspirin

Antithrombotic agents have received a good deal of attention in the management of HWD. Potential benefits include reduction in severity of vascular lesions, reduction in thromboxane-induced pulmonary arterial vasoconstriction and PHT, and minimization of postadulticidal PTE. Aspirin has shown success in diminishing the vascular damage caused by segments of dead worms, reduced the extent and severity of myointimal proliferation caused by implanted living worms, and improved pulmonary parenchymal disease and intimal proliferation in dogs receiving thiacetarsemide after previous living heartworm implantation. More recent studies, however, have produced controversial results. Four dogs with implanted heartworms, receiving adulticide and administered aspirin, showed no improvement in pulmonary angio-graphic lesions, and treated dogs had more severe tortuousity than did controls and dogs receiving heparin. Boudreau and colleagues demonstrated that the aspirin dose required to decrease platelet reactivity by at least 50% was increased by nearly 70% with heartworm infection (implantation model) and by nearly 200% with a model (dead worm implantation) of PTE. There were not significant differences in severity of pulmonary vascular lesions in aspirin-treated versus control dogs. For these reasons, the American Heartworm Society does not endorse antithrombotic therapy for routine treatment of HWD. Calvert and colleagues have, however, successfully used the combination of aspirin and strict cage confinement with adul-ticidal therapy for severe HWD.

If used, aspirin is administered daily beginning 1 to 3 weeks prior to and continued for 4 to 6 weeks after adulticide administration. With protracted aspirin therapy, packed cell volume (PCV) and serum total protein, should be monitored periodically. Aspirin is avoided or discontinued in the face of gastrointestinal (GI) bleeding (melena or falling PCV), persistent emesis, thrombocytopenia (50,000/mm), and hemoptysis.

Heparin Therapy

Low-dose calcium heparin has been studied in canine heartworm disease and shown to reduce the adverse reactions associated with thiacetarsemide in dogs with severe clinical signs, including heart failure. In this study, calcium heparin administered at 50 to 100 IU/kg subcutaneously every 8 to 12 hours for 1 to 2 weeks before and 3 to 6 weeks after adulticidal therapy, reduced thromboembolic complications and improved survival, as compared with aspirin and indobufen. Dogs in both groups also received prednisone at 1 mg/kg/day. It is emphasized that this therapy has not been studied with melarsomine adulticidal therapy. Calvert and colleagues advocate sodium heparin (50 to 70 U/kg) in dogs with thrombocytopenia, DIC, or both, continuing until the platelet count is greater than 150,000/mm, for at least 7 days, and possibly for weeks.

Microfilaricidal Therapy

Despite the fact that no agent is approved by the Food and Drug Administration for the elimination of microfilaria, microfilaricidal therapy is traditionally instituted 4 to 6 weeks after adulticide administration. The macrolides offer a safe and effective alternative to levamisole and dithiazanine. Microfilariae are rapidly cleared with ivermectin at 50 ug/kg (approximately eight times preventative dose) or milbemycin at 500 mg/kg (preventative dose), although this represents an extra-label use of ivermectin. Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 6% of 126 dogs receiving ivermectin at the microfilaricidal dose. Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2 to 4 mg/kg intravenously) therapy, all dogs recovered within 12 hours. One fatality, however, was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dose. Dogs so treated should be hospitalized and carefully observed for the day. Dogs less than 16 kg, harboring more than 10,000 microfilaria per milliliter of blood, are more apt to suffer adverse reactions. Benadryl (2 mg/kg intramuscularly) and dexamethasone (0.25 mg/kg intravenously) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides.

A slower microfilarial kill rate can also be achieved with ivermectin, moxidectin, and selamectin at preventative doses. Using either the rapid or “slow kill” approach rids the patient of microfilariae and sterilizes the female heartworm.

The American Heartworm Society recommends that macrolide therapy, at preventative doses, be instituted 3 to 4 weeks after adulticidal therapy. Accelerated microfilaria] destruction can be achieved using recommended doses of milbemycin or by reducing the dosing interval for the other topical or oral formulations to every 2 weeks. Filter or modified Knott tests are rechecked in 5 months when using a slow kill or after 2 to 3 macrolide doses when using a accelerated dose. This interval for testing can be reduced if milbemycin or high-dose ivermectin (50 ug/kg) is chosen.

This author chooses an alternative approach (), beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy. With the slow kill microfilaricides (ivermectin, moxidectin, or selamectin at preventative doses), little chance exists of an adverse reaction; however, the owner is warned of the possibility and advised to administer the medication on a day when he or she will be at home. If milbemycin is used, it is usually administered in the hospital and may be preceded by administration of dexamethasone and Benadryl (as described previously in adulticidal therapy).

Categories
Diseases

Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.

Glomerulonephritis

The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.

Categories
Drugs

Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.

Pharmacology/Actions

Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.

Pharmacokinetics

Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()

Monitoring

■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)