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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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Diseases

Diseases of the Throat: Diagnosis

Diagnostic Imaging

Lateral and ventrodorsal radiographic views of both the skull and cervical areas are indicated. Radiopaque foreign bodies can be identified that may be missed on laryngoscopy and pharyngoscopy (e.g. sewing needle embedded in soft tissues). Radiographs are also useful in identifying bony changes associated with chronic inflammation or neoplasia, identifying clues of unreported trauma (e.g. subcutaneous emphysema), and occasionally soft tissue masses. Suggestion of a soft tissue mass is confirmed by direct visualization and histopathology. Thoracic radiographs are also indicated. Symptoms of lower respiratory disease may be masked when a patient has concurrent, and more severe, upper respiratory symptoms. Evaluation for aspiration pneumonia, metastases, or suggestion of a motility disorder (i.e. megaesophagus) is possible.

Ultrasonography and computed tomography (CT) are noninvasive modalities to evaluate the pharynx and larynx. Ultrasonography can identify soft tissue masses, help guide fine needle aspiration, and evaluate laryngeal function. The presence of air in these areas can limit the usefulness of this modality in establishing a definitive diagnosis. CT may be used to fully evaluate involvement of neoplasia or middle-ear disease if a nasopharyngeal polyp is suspected.

Videofluoroscopy is essential for any case of dysphagia. A barium swallow allows the act of swallowing to be recorded and studied for abnormalities. The patient should be recorded attempting to swallow barium to mimic liquids and then should be given a meal (canned food mixed with barium) to be recorded. Videofluoroscopy is superior to radiography because it allows all phases of deglutition to be evaluated instead of recording one moment (intermittent moments) of the event. Unfortunately videofluoroscopy is limited to referral centers only.

Pharyngoscopy and Laryngoscopy

Laryngoscopy and pharyngoscopy allow assessment of both structural abnormalities and function of the larynx. A flexible endoscope is used for these procedures because visualization of the nasopharynx requires retroflexion. Occasionally a foreign body will be found just caudal to the larynx and may be retrieved endoscopically. The patient is placed in sternal recumbency and anesthetized with either propofol or sodium thiopental. Once anesthetized, gauze is passed under the maxilla behind the canine teeth. The gauze is used to elevate the head, so external compression of the neck is avoided. Flexible endoscopy is ideal to evaluate the nasopharynx. If that is not possible, the caudal pharynx can be evaluated using a dental mirror and a snook hook. This will be sufficient in evaluating most nasopharyngeal polyps, masses, or caudal foreign bodies. It will not allow diagnosis of more rostral diseases such as nasopharyngeal stenosis. Laryngeal function is usually evaluated first by assessing the motion of the arytenoid cartilages. The traditional approach involves titrating anesthesia that allows both visualization of the arytenoid cartilages and deep spontaneous breaths to occur. In a normal animal the arytenoid cartilages will abduct symmetrically with each inspiration and close on expiration. The frustration with this technique is multiple. Maintaining the correct level of anesthesia is difficult (i.e. the animal is too awake to allow adequate visualization of the arytenoid cartilages or anesthetized so that the patient will not spontaneously breathe); shallow breathing can limit adequate assessment; and concerns about the effect of anesthesia on laryngeal function are legitimate concerns when performing the traditional laryngeal examination. The recently introduced technique attempts to eliminate the effects of anesthesia from the examination. Patients are premedicated with acepromazine maleate and butorphanol tartrate and induced with propofol. Doxapram hydrochloride (2.2 mg/kg intravenously) is used to increase laryngeal motion and minimize or eliminate the effects of anesthesia,

Miscellaneous

Hematology and biochemical profiles should be performed on patients with pharyngeal and laryngeal dysfunction, but they will rarely confirm the definitive diagnosis. Occasionally virus isolation (feline calicivirus (FCV)) and PCR (feline herpes-1 virus (FHV-1), Chlantydia spp. and Mycoplasma spp.) are indicated in the diagnostic workup. Culture and sensitivity of tissue or secretions can provide valuable information during the diagnostic workup. Cytology and histopathology are also essential for critically evaluating infiltrative disease or mass lesions.

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Diseases

Hypertrophic Cardiomyopathy: Acute Therapy

Just as with dilated cardiomyopathy, cats that have respiratory distress suspected of having heart failure secondary to hypertrophic cardiomyopathy may need to be placed in an oxygen-enriched environment as soon as possible. If possible the cat should be initially evaluated by doing a cursory physical examination, taking care not to stress the patient during this or any other procedure, because stress exacerbates dyspnea and arrhythmias and often leads to death. Most, but not all, cats with severe hypertrophic cardiomyopathy that are in heart failure will have a heart murmur and gallop rhythm. A butterfly catheter should be used to perform thoracentesis on both sides of the chest to look for pleural effusion as soon as possible. Generally this should be done with the cat in a sternal position so that it does not become stressed during the procedure. Clipping of the hair is not needed. If fluid is identified, it should be removed. Most cats that arc dyspneic due to pleural effusion have 150 to 250 mL of fluid in their pleural space. If none is identified, a lateral thoracic radiograph to identify pulmonary edema may be taken with the veterinarian present to ensure that the cat is not stressed (e.g., the clinician should make sure no one stretches the cat out or in any way interferes with its ability to breathe). If the patient struggles or appears to be stressed or fractious during or before radiographic examination, the procedure should be canceled and the patient placed into an oxygen-enriched environment. A preferable alternative to blind tapping is to perform a superficial ultrasonographic examination to identify and locate fluid accumulation.

Furosemide

Furosemide should initially be administered intravenously or intramuscularly to the cat in severe respiratory distress. The route of administration depends on the stress level of the patient. Furosemide should bo administered intramuscularly to cats that are very distressed and cannot tolerate restraint for an intravenous injection. Cats that can tolerate an intravenous injection may benefit from the more rapid onset of action (within 5 minutes of an intravenous injection versus 30 minutes for an intramuscular injection).The initial rurosemide dose to a cat in distress should generally be in the 1 to 2 mg/lb range, intramuscularly or intravenously. This dose may be repeated within 1 hour to 2 hours ().

High-dose parenteral furosemide therapy commonly produces electrolyte disturbances and dehydration in cats. Cats with severe heart failure that require intensive therapy are often precarious. They may be presented dehydrated and electrolyte-depleted because of anorexia. They may remain anorexic and consequently dehydrated and depleted of electrolytes once the edema, the effusion, or both are lessened. Judicious intravenous or subcutaneous fluid administration may be required to improve these cats clinically. Overzealous fluid administration will result in the return of congestive heart failure. If fluid administration is required, the furosemide administration must be discontinued for that time.

Nitroprusside

Anecdotally, nitroprusside may be beneficial in cats with severe pulmonary edema due to hypertrophic cardiomyopathy. As with dilated cardiomyopathy, it may be administered empirically at 2 ug/lb/min or titrated, using blood pressure measurement to document efficacy, starting at a dose of 1 to 2 pg/lb/min. Nitroprusside has a very short half-life. Consequently, if clinically significant systemic-hypotension is produced (e.g., weakness, collapse, poor capillary refill time) cessation of the infusion will result in the systemic blood pressure returning to normal within several minutes.

Nitroglycerin

Nitroglycerin cream may be beneficial in cats with severe edema formation secondary to feline cardiomy-opathy. However, no studies have examined effects or efficacy. Nitroglycerin is safe and some benefit may occur with its administration in some cats. Consequently, one-eighth inch to one-fourth inch of a 2% cream may be administered to the inside of an ear every 4 to 6 hours for the first 24 hours as long as furosemide is being administered concomitandy. Nitroglycerin is not a primary drug. Tolerance develops rapidly in other species, and prolonged administration is probably of even lesser benefit.

Once drug administration is complete, the cat should be left to rest quietly in an oxygen-enriched environment. Care should be taken not to distress the cat. A baseline measurement of the respiratory rate and assessment of respiratory character should be taken when the cat is resting. This should be followed at 30-minute intervals and furosemide administration continued until the respiratory rate starts to decrease (a consistent decrease of the respiratory rate from 70 to 90 breaths per minute into the 50 to 60 breaths per minute range is a general guide), the character of the cat’s respiratory effort improves, or both occur. When this happens, the furosemide dose and dose frequency should be curtailed sharply.

Sedation or Anesthesia

In some cats, sedation with acepromazine (0.02 to 0.5 mg/lb intramuscularly or intravenously) may help by producing anxiolysis. Oxymorphone (0.02 to 0.04 mg/lb every 6 hours intramuscularly, intravenously, or sub-cutaneously) or butorphanol tartrate (0.04 mg/lb intravenously or 0.18 mg/lb every 4 hours subcutaneously) may also be used but are secondary choices because they can produce respiratory depression. Oxymorphone may produce excitement in some cats.

In some cats with fulminant heart failure, anesthesia, intubation, and ventilation are required to control the respiratory failure. Although this method is not preferred for most severely dyspneic cats, it can be life saving in some. This procedure has the advantage of being able to administer 100% oxygen and to be able to drain or suction fluid from the large airways in a controlled environment. The disadvantage is the administration of anesthetic agents to a cat that has cardiovascular compromise.

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Diseases

Treatment of Systemic Arterial Thromboembolism

Euthanasia In cats that are in acute pain that have a poor prognosis due to severe cardiomyopathy, euthanasia is a humane means of dealing with the problem. Systemic throm-boembolism is often a horrible complication of cardiomyopathy, the treatment options are all relatively poor, and rethrombosis is common. Consequently, although one should not automatically give up on a patient, one should not give false hope either.

Pain Control Cats that present in pain must be treated appropriately for their pain. Appropriate drugs include a fentanyl patch, oxymorphone (intramuscularly, intravenously, or subcutaneously) and butorphanol tartrate (subcutaneously). Aspirin does not produce adequate pain control. Oxymorphone may produce excitement in some cats. The analgesic properties of butorphanol are five times that of morphine, and it remains a nonscheduled drug by the Food and Drug Administration. Its respiratory depressant effects equal that of morphine. Consequently, one must be careful when administering this drug to a patient with dyspnea. Acepromazine may be administered intravenously in addition as an anxiolytic agent to cats that still appear distressed after the administration of the analgesic or to cats that become agitated after oxymorphone administration. The pain abates with time (usually hours) as sensory nerves undergo necrosis.

Palliative Therapy Beyond pain control, many cats with systemic arterial thromboembolism receive only supportive care or the administration of drugs with no proven benefit. The primary outcome of arterial occlusion depends upon the extent of occlusion and the time to spontaneous reperfusion. Poor prognostic factors for short-term survival include worsening azotemia, moderate to severe pulmonary edema or pleural effusion, malignant arrhythmias, severe hypothermia, disseminated intravascular coagulation, and evidence of multiorgan embolization. Long-term, cats may lose an affected leg because of ischemic necrosis, die of toxemia, remain paralyzed from peripheral nerve damage, or regain full or partial function of their legs. About 50% of cats that are not treated definitively will regain all or most caudal limb motor function within 1 to 6 weeks. Return of function presumably is due to the cat’s own thrombolytic system (e.g., plasmin) disrupting the thromboembolus. The degree and rapidity of the dissolution depend on the activity of a particular cat’s thrombolytic system and the size and quality of the thromboembolus. Usually, cats that have some evidence of caudal limb flow recover more rapidly than do cats with no evidence of flow. Presumably this is because the size of the thromboembolus in cats with some flow is smaller. With total occlusion, some cats recanalize within days (others never recanalize).This extreme variability makes it very difficult to render a prognosis for a particular patient at presentation.

Palliative therapy may be only cage rest and pain control or can include administering drugs such as heparin, aspirin, or arteriolar dilators along with the cage rest. No drugs administered for palliation have any proven benefit over cage rest alone.

Heparin is commonly administered in the hopes of preventing new thrombus formation on top of the existing thromboembolus or in the hope of preventing a new thrombus from forming in the left atrium. However, no evidence indicates that heparin is of benefit in cats with STE. Heparin does not aid in thrombolysis. Heparin can be administered at an initial dose of 100 U/lb intravenously followed by a maintenance dose of 30 to 100 U/lb subcutaneously every 6 hours. The dose should be tailored to each individual cat to increase the activated partial thromboplastin time (aPTT) to at least 1.5 times baseline.

Indomethacin is effective at preventing vasoconstriction distal to the thromboembolus when administered to experimental cats prior to creating an aortic thrombus. Theoretically aspirin could do the same thing. However, no evidence indicates that it improves collateral blood flow.

The administration of drugs that dilate systemic arterioles (e.g., hydralazine, acepromazine) has been advocated. These drugs act by relaxing the smooth muscle in systemic arterioles. The exact anatomy of collateral vessels is not well described, but they are probably larger vessels than arterioles. They contain smooth muscle, because they can open and close. The ability of arteriolar dilators to counteract serotonin and thromboxane A2-induced vasoconstriction is unknown.

Definitive Therapy Definitive treatments for systemic arterial thromboembolism in cats include administration of exogenous fibrinolytic agents, balloon embolectomy, rheolytic thrombectomy, and surgery. All definitive procedures are associated with high mortality and common recurrence of the thromboembolus days to months after the initial removal.

Surgery Surgical removal of systemic thromboemboli is generally thought to be associated with high mortality and is not frequently performed. Cats with systemic arterial thromboembolism commonly have underlying cardiac disease, and many are in heart failure. They are poor anesthetic risks, and reperfusion syndrome may be produced. In reperfusion syndrome the muscles of the legs prior to removal of the systemic arterial thromboembolism undergo necrosis, cellular breakdown, and the release of potassium and hydrogen ions from the cells into the interstitial spaces. Sudden reperfusion carries these ions into the systemic circulation, causing acute and often severe hyperkalemia and metabolic acidosis. Surgical intervention may be a viable option if careful monitoring and treatment for reperfusion syndrome with insulin and glucose, sodium bicarbonate, or calcium (or a combination of these therapies) can be initiated immediately if it occurs.

Balloon embolectomy The procedure of choice in human medicine is balloon embolectomy. The author has had limited experience with balloon embolectomy. In this procedure the femoral arteries are isolated and a small balloon embolec-tomy catheter is passed from one femoral artery into the aorta. The femoral arteries are not extremely difficult to isolate. The catheter is pushed past the thromboembolus, and the balloon is then inflated and the catheter withdrawn, along with throm-boembolic material. The catheter is passed sequentially, first in one artery and then in the other. Usually this sequence must be repeated several times. Reperfusion syndrome may occur with balloon embolectomy.

Thrombolytic therapy Thrombolytic therapy is a possible means of dealing with cats with systemic arterial thromboembolism using fibrinolytic agents. Thromboemboli in cats are composed of red cells, strands of fibrin, and possibly platelets. Fibrinolytic agents cleave plas-minogen to plasmin. Plasmin hydrolyzes fibrin, resulting in thrombolysis. Different agents vary in their ability to bind specifically to fibrin-bound plasminogen and in their half-lives. Efficacy and complication rates appear to be very similar in humans. Complications consist primarily of hemorrhage due to fibrinolysis and rethrombosis. Fibrinolytic agents can be very effective at lysing systemic thromboemboli. However, the author and colleagues currently treat few cats with systemic arterial thromboembolism with these agents because reperfusion syndrome and rethrombosis are common.

Tissue plasminogen activator (t-PA) and streptokinase have been used in cats. Tissue plasminogen activator is an intrinsic protein present in all mammals. Numerous reports exist of the use of t-PA for the lysis of thrombi as therapy for acute myocardial infarction, pulmonary thromboembolism, and peripheral vascular obstruction in humans and experimental animals. The activity of genetically engineered t-PA in feline plasma is 90% to 100% of that seen in human plasma. The half-life of t-PA is quite short. Heparin must be administered concomitandy to prevent acute rethrombosis but does not need to be administered with streptokinase because it has a longer half-life. A clinical trial with t-PA in cats with aortic thromboemboli has shown acute thrombolytic efficacy (shortened time to reperfusion and ambulation) associated with the administration of t-PA at a rate of 0.1 mg to 0.4 mg/lb/hr for a total dose of 0.4 to 4 mg/lb intravenously. Forty three percent of cats treated survived therapy and were walking within 48 hours of presentation. Post-t-PA angiograms demonstrated resolution of the primary vascular occlusion. Thus acutely, t-PA effectively decreases the time to reperfusion and return to function in cats with aortic thromboemboli. However, 50% of the cats died during therapy in this clinical trial, which raises extreme concerns regarding acute thrombolysis. Fatalities resulted from reperfusion syndrome (70%), congestive heart failure (15%), and sudden arrhythmic death, presumably the result of embolization of a small thrombus to a coronary artery (15%). Severe hemorrhage into the region distal to the systemic arterial thromboembolism causing anemia was also a common complication. The cats that successfully completed t-PA therapy exhibited signs of increasing neuromuscular function and ambulatory ability within 2 days of presentation. This contrasts with 1 to 6 weeks before seeing similar signs of improvement in most cats exhibiting spontaneous resolution.

Mortality due to reperfusion syndrome can be reduced if the patient can be observed continuously by an individual trained to identify clinical and electrocardiographic evidence of hyperkalemia, if intensive monitoring of electrolytes and blood pH can be performed, and if aggressive medical therapy for hyperkalemia and metabolic acidosis can be initiated very quickly. This means dedicated care 24 hours a day until the thromboembolus is lysed. Thrombolysis may occur within 3 hours or take as long as 48 hours.

If reperfusion syndrome was the only major complicating factor in cats treated with thrombolytic agents, continued use in selected patients might be warranted. However, 90% of the cats that were successfully treated in the aforementioned clinical trial

had another systemic arterial thromboembolism within 1 to 3 months. Rethromboembolism occurred despite aspirin, warfarin, or heparin administration. In addition, t-PA is expensive. Consequently, the author does not currently use t-PA for systemic arterial thromboembolism in cats.

Streptokinase has clinical efficacy very similar to t-PA in human patients with coronary artery thrombosis. Streptokinase is less expensive. No controlled clinical trials of streptokinase use for systemic arterial thromboembolism in cats are available, and the author’s clinical experience with the drug has been generally negative. There has been one small experimental study in which throm-bin was injected between two ligatures placed at the terminal aorta to create a soft thrombus, followed by removal of the ligatures. Streptokinase was administered as a loading dose at 90,000 III followed by 45,000 IU/hr for 3 hours. This dose produced evidence of systemic fibrinolysis in a separate group of normal cats but without evidence of severe fibrinolysis or bleeding. In most cats there was no angiographic change and no improvement in limb temperature. There was a tendency for the thrombus weight to be lower in the treated cats when compared with control cats at postmortem examination. However, lysis of a fresh thrombus created with thrombin is probably much different from trying to lyse an established thromboembolus. Streptokinase is usually unsuccessful, may hasten the death of some cats through bleeding complications, and should not be routinely used.

Rheolytic thrombectomy Rheolytic thrombectomy is an experimental catheter-based system used for the dissolution of the thromboembolus using a high-velocity water jet at the end of the catheter that breaks up the thromboembolus and sucks it back into the system using the Venturi effect. Anesthesia is required and blood transfusion is almost always needed. The catheter is passed from the carotid artery to the region of the thromboembolus. The author and colleagues have used it in six cats. The procedure successfully removed the thromboembolus in five cats but only three left the hospital. Time from onset of clinical signs to thrombectomy was several hours to 8 days. The cat that had the procedure 8 days after the event had residual neurologic deficits but was the longest survivor. Interestingly, reperfusion syndrome has not been a common complication.

Adjunctive therapy Cats with systemic arterial thromboembolism are commonly in heart failure at the time of presentation. Medical therapy with furosemide and an angiotensin-converting enzyme inhibitor is often indicated. Cats that are in pain usually do not eat or drink. Fluid therapy is warranted but must not aggravate or produce heart failure

Cats that take a long time to recover caudal limb function or that only attain partial function may develop regions of skin and muscle necrosis, especially on the distal limbs. These regions may need to be debrided surgically. Cats that lose the function of only one leg or that do not regain function of one leg benefit from amputating that leg. Cats that have perma-nendy lost muscle function distal to the hock may benefit from arthrodesis.

Prognosis The short-term prognosis for life is guarded in cats without heart failure. Cats with a rectal temperature lower than 98.9° F had a worse prognosis in one study. Ifi The long-term prognosis is highly variable and depends on the ability to control the heart failure and the events surrounding the STE. One of the most common causes of death within the first 24 hours is euthanasia. In one study, cats lived between 3 and 30 months after the initial episode. The average survival time was about 10 to 12 months. In another study, MST for cats that recovered and were discharged from the hospital was approximately 4 months but was only about 2.5 months in cats that were also being treated for heart failure. The long-term prognosis for limb function depends on the ability of the cat to lyse its own clot or on the success of intervention. Many biologic variables determine whether or not reperfusion will spontaneously occur. A significant percentage of cats will develop a new thromboembolus, days to months after recovery.

Prophylaxis Feline patients with myocardial disease, especially those with an enlarged left atrium, should be considered at risk for developing intracardiac thrombi and signs of peripheral arterial thromboembolism, although the incidence appears to be low. Preventing peripheral thrombosis is, in theory, one of the most important therapeutic objectives for the veterinarian managing cats with severe myocardial disease. The ideal means of preventing thrombosis is resolution of the underlying myocardial disease. This is usually only possible in a cat with dilated cardiomyopathy secondary to taurine deficiency.

At-present, the only option available is to manipulate the patient’s coagulation system in an attempt to alter the delicate balance between the pathways that promote clotting and those that inhibit thrombus formation to reduce the patient’s thrombogenic potential. At this time, antiplatclet and anticoagulant therapies are the only means of preventing thrombus formation in cats with myocardial disease. Unfortunately, they are often ineffective and, in the case of warfarin, can produce serious side effects. Experience is similar in human medicine.

Antiplatelet therapy Prostaglandins enhance platelet aggregation via activation of cyclic adenosine monophosphate (cAMP). Aspirin (acetylsalicylic acid) acetylates platelet cyclooxygenase, preventing the formation of thromboxane A2, a potent prostaglandin-like platelet aggregating substance. The inhibition of platelet cyclooxygenase is irreversible, and bleeding time is restored to normal only after the production of new platelets. The inhibition of endothelial cyclooxygenase is reversible. The dose of aspirin recommended in cats is 10 mg/lb every third day. Whether or not this dose allows endothelial cyclooxygenase to recover or not in cats is undetermined. At this dose, aspirin has a half-life of 45 hours in the cat. In humans, doses as low as 20 to 100 mg/day inhibit platelet cyclooxygenase; however, no evidence suggests that this low dose has any more benefit than conventional daily doses of 625 to 1250 mg. In one study in cats, no difference was seen in thromboembolus recurrence between cats on low dose (5 mg/cat every 72 hours) and high dose (greater than or equal to 40 mg/cat every 72 hours). No evidence indicates that any dose of aspirin is effective at preventing the formation of an intracardiac thrombus in cats with myocardial disease. Clinical impression of aspirin’s efficacy varies between clinicians. Cats that have already experienced one systemic arterial thromboembolism are the only appropriate population in which to study the efficacy of an agent meant to prevent STE. Aspirin does not prevent recurrence of peripheral thromboembolism in this population.

Glycoprotein IIb and IIIa, an integrin present on platelet surfaces, is a receptor for fibrinogen, fibronectin, and von Willebrand factor. It mediates aggregation, adhesion, and spreading of platelets. The binding of prothrombin to glycoprotein IIb and IIIa also enhances the conversion of prothrombin to thrombin. Glycoprotein IIb and IIIa antagonists have been developed, and one (abciximab) increased mucosal bleeding time and reduced thrombus area when combined with aspirin (when compared with aspirin and placebo).

Anticoagulant therapy Available anticoagulants include heparin, the low molecular weight heparins, and warfarin. Heparin binds to a lysine site on AT, producing a conformational change at the arginine-reactive site that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of thrombin and factor Xa. AT binds covalently to the active serine centers of coagulation enzymes. Factor Xa bound to platelets and thrombin bound to fibrin are protected from activation by the heparin-antithrombin III complex. Heparin may be administered intravenously or subcutaneously. Repeated intramuscular injection is discouraged because local hemorrhage may result. Some owners can administer heparin subcutaneously at home but the method is not ideal. The author and colleagues have noted rethrombosis with heparin therapy in some cats with cardiac disease. The dose of heparin for preventing thrombosis in cats is unknown.

Low molecular weight heparins include nadroparin calcium, enoxaparin sodium, dalteparin, ardeparin, tinzaparin, reviparin, and danaparoid sodium. The low molecular weight heparins have fewer bleeding complications in experimental animals, improved pharmacokinetics over heparin, are administered subcutaneously, and do not require monitoring in most situations. Although heparin does not reduce red cell aggregation in slow-moving blood, heparin and low molecular weight heparins are effective at preventing deep vein thrombosis in humans. Consequently, they may be beneficial in preventing intracardiac thrombus formation in cats with cardiomyopathy. No controlled studies are available. The author empirically uses enoxaparin sodium at a dose of 2.2 mg/lb every 12 hours subcutaneously in cats that have recovered from an systemic arterial thromboembolism or that have a severely enlarged left atrium and SEC.

Warfarin sodium is an oral anticoagulant (). Warfarin exerts no anticoagulant effect in vitro. In vivo, inhibitory effects on synthesis of clotting factors begin immediately. However, clotting is unaffected until already existing clotting factors decline. Therefore a delay occurs between initial administration and effect on the prothrombin time (FT). Historically, oral warfarin therapy has been monitored with the PT.This test measures the activity of factors II, VII, and X. The factor depressed most quickly and profoundly (usually factor VII) determines the FT during the initial days of therapy. The FT is performed by measuring the clotting time of platelet-poor plasma after the addition of thromboplastin and calcium, a combination of tissue factor and phospholipid. Intra- and interlaboratory variation in the FT was a significant problem for laboratories in the past, when crude extracts of human placenta or rabbit brain were the only source of thromboplastin. The international normalized ratio (INR), developed by the WHO in the early 1980s, is designed to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different lots of thromboplastin. The INR is used worldwide by most laboratories performing oral anticoagulation monitoring and is routinely incorporated into dose planning for human patients receiving warfarin. When the anticoagulant effect is excessive, it can be counteracted by administering vitamin K,. However, once synthesis of factors 11, VII, IX, and X is reinstituted, time must elapse before factors achieve concentrations in the plasma that will adequately reverse the bleeding tendency. If serious bleeding occurs during therapy with warfarin, it may be stopped immediately by administering fresh blood or plasma that contains the missing clotting factors. Other drugs can modify the anticoagulant actions of warfarin by altering the bioavailability of vitamin K by altering the absorption, distribution, or elimination of the coumarins; by affecting synthesis or degradation of clotting factors; or by altering protein binding of the warfarin. The maintenance dose should be evaluated daily during the initial titration (3 days), then every other day (twice), and then weekly until a safe and stable dose regimen is determined. The therapeutic effect should be reevaluated periodically (at least once per month). The recommended initial dose is 0.1 to 0.2 mg per cat every 24 hours orally to a 6 to 10 lb/cat. The dose may then be increased to maintain an INR of 2.0 to 3.0. It can take up to 1 week for new steady state conditions to be achieved. The efficacy of warfarin at preventing recurrent thrombosis in cats with cardiac disease has been reported. M-s In one report, out of 23 cats examined retrospectively, 10 experienced a new thromboembolic episode while being administered warfarin. Two of these cats had at least two new episodes. In the other report, eight of 18 cats on warfarin experienced a new thromboembolic episode. This may be some improvement over the 75% recurrence rate reported for aspirin alone after t-PA therapy, but these results are still disappointing.i:,h In the first report, four cases also died suddenly (which could have been caused by thromboembolLsm). Three of these cats did not have postmortem examinations. The one cat that did have a postmortem examination had a thrombus present in its left atrium. One cat also died of a renal infarct that produced renal failure. Four cats appeared to have bleeding complications. In the second report, one cat died of a hemoabdomen and one was suspected to have an acute intracranial hemorrhage resulting in death. Consequendy, it appears that warfarin therapy can produce fatal complications. However, it should be noted that these studies were performed without using the INR for monitoring.

Categories
Drugs

Acepromazine Maleate (PromAce, Aceproject)

Phenothiazine Sedative / Tranquilizer

Highlights Of Prescribing Information

Negligible analgesic effects

Dosage may need to be reduced in debilitated or geriatric animals, those with hepatic or cardiac disease, or when combined with other agents

Inject IV slowly; do not inject into arteries

Certain dog breeds (e.g., giant breeds, sight hounds) may be overly sensitive to effects

May cause significant hypotension, cardiac rate abnormalities, hypo- or hyperthermia

May cause penis protrusion in large animals (esp. horses)

What Is Acepromazine Used For?

Acepromazine is approved for use in dogs, cats, and horses. Labeled indications for dogs and cats include: “… as an aid in controlling intractable animals… alleviate itching as a result of skin irritation; as an antiemetic to control vomiting associated with motion sickness” and as a preanesthetic agent. The use of acepromazine as a sedative/tranquilizer in the treatment of adverse behaviors in dogs or cats has largely been supplanted by newer, effective agents that have fewer adverse effects. Its use for sedation during travel is controversial and many no longer recommend drug therapy for this purpose.

In horses, acepromazine is labeled “… as an aid in controlling fractious animals,” and in conjunction with local anesthesia for various procedures and treatments. It is also commonly used in horses as a pre-anesthetic agent at very small doses to help control behavior.

Although not approved, it is used as a tranquilizer (see doses) in other species such as swine, cattle, rabbits, sheep and goats. Acepromazine has also been shown to reduce the incidence of halothane-induced malignant hyperthermia in susceptible pigs.

Before you take Acepromazine

Contraindications / Precautions / Warnings

Animals may require lower dosages of general anesthetics following acepromazine. Use cautiously and in smaller doses in animals with hepatic dysfunction, cardiac disease, or general debilitation. Because of its hypotensive effects, acepromazine is relatively contraindicated in patients with hypovolemia or shock. Phenothiazines are relatively contraindicated in patients with tetanus or strychnine intoxication due to effects on the extrapyramidal system.

Intravenous injections should be made slowly. Do not administer intraarterially in horses since it may cause severe CNS excitement/depression, seizures and death. Because of its effects on thermoregulation, use cautiously in very young or debilitated animals.

Acepromazine has no analgesic effects; treat animals with appropriate analgesics to control pain. The tranquilization effects of acepromazine can be overridden and it cannot always be counted upon when used as a restraining agent. Do not administer to racing animals within 4 days of a race.

In dogs, acepromazine’s effects may be individually variable and breed dependent. Dogs with MDR1 mutations (many Collies, Australian shepherds, etc.) may develop a more pronounced sedation that persists longer than normal. It may be prudent to reduce initial doses by 25% to determine the reaction of a patient identified or suspected of having this mutation.

Acepromazine should be used very cautiously as a restraining agent in aggressive dogs as it may make the animal more prone to startle and react to noises or other sensory inputs. In geriatric patients, very low doses have been associated with prolonged effects of the drug. Giant breeds and greyhounds may be extremely sensitive to the drug while terrier breeds are somewhat resistant to its effects. Atropine may be used with acepromazine to help negate its bradycardic effects.

In addition to the legal aspects (not approved) of using acepromazine in cattle, the drug may cause regurgitation of ruminal contents when inducing general anesthesia.

Adverse Effects

Acepromazine’s effect on blood pressure (hypotension) is well described and an important consideration in therapy. This effect is thought to be mediated by both central mechanisms and through the alpha-adrenergic actions of the drug. Cardiovascular collapse (secondary to bradycardia and hypotension) has been described in all major species. Dogs may be more sensitive to these effects than other animals.

In male large animals acepromazine may cause protrusion of the penis; in horses, this effect may last 2 hours. Stallions should be given acepromazine with caution as injury to the penis can occur with resultant swelling and permanent paralysis of the penis retractor muscle. Other clinical signs that have been reported in horses include excitement, restlessness, sweating, trembling, tachypnea, tachycardia and, rarely, seizures and recumbency.

Its effects of causing penis extension in horses, and prolapse of the membrana nictitans in horses and dogs, may make its use unsuitable for show animals. There are also ethical considerations regarding the use of tranquilizers prior to showing an animal or having the animal examined before sale.

Occasionally an animal may develop the contradictory clinical signs of aggressiveness and generalized CNS stimulation after receiving acepromazine. IM injections may cause transient pain at the injection site.

Overdosage / Acute Toxicity

The LD50 in mice is 61 mg/kg after IV dosage and 257 mg/kg after oral dose. Dogs receiving 20-40 mg/kg over 6 weeks apparently demonstrated no adverse effects. Dogs gradually receiving up to 220 mg/kg orally exhibited signs of pulmonary edema and hyperemia of internal organs, but no fatalities were noted.

There were 128 exposures to acepromazine maleate reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases, 89 were dogs with 37 showing clinical signs and the remaining 39 reported cases were cats with 12 cats showing clinical signs. Common findings in dogs recorded in decreasing frequency included ataxia, lethargy, sedation, depression, and recumbency. Common findings in cats recorded in decreasing frequency included lethargy, hypothermia, ataxia, protrusion of the third eyelid, and anorexia.

Because of the apparent relatively low toxicity of acepromazine, most overdoses can be handled by monitoring the animal and treating clinical signs as they occur; massive oral overdoses should definitely be treated by emptying the gut if possible. Hypotension should not be treated with epinephrine; use either phenylephrine or norepinephrine (levarterenol). Seizures may be controlled with barbiturates or diazepam. Doxapram has been suggested as an antagonist to the CNS depressant effects of acepromazine.

How to use Acepromazine

Note: The manufacturer’s dose of 0.5-2.2 mg/kg for dogs and cats is considered by many clinicians to be 10 times greater than is necessary for most indications. Give IV doses slowly; allow at least 15 minutes for onset of action.

Acepromazine dosage for dogs:

a) Premedication: 0.03-0.05 mg/kg IM or 1-3 mg/kg PO at least one hour prior to surgery (not as reliable) ()

b) Restraint/sedation: 0.025-0.2 mg/kg IV; maximum of 3 mg or 0.1-0.25 mg/kg IM; Preanesthetic: 0.1-0.2 mg/kg IV or IM; maximum of 3 mg; 0.05-1 mg/kg IV, IM or SC ()

c) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

d) 0.55-2.2 mg/kg PO or 0.55-1.1 mg/kg IV, IM or SC (Package Insert; PromAce — Fort Dodge)

e) As a premedicant with morphine: acepromazine 0.05 mg/kg IM; morphine 0.5 mg/kg IM ()

Acepromazine dosage for cats:

a) Restraint/sedation: 0.05-0.1 mg/kg IV, maximum of 1 mg ()

b) To reduce anxiety in the painful patient (not a substitute for analgesia): 0.05 mg/kg IM, IV or SC; do not exceed 1 mg total dose ()

c) 1.1-2.2 mg/kg PO, IV, IM or SC (Package Insert; PromAce — Fort Dodge)

d) 0.11 mg/kg with atropine (0.045-0.067 mg/kg) 15-20 minutes prior to ketamine (22 mg/kg IM). ()

Acepromazine dosage for ferrets:

a) As a tranquilizer: 0.25-0.75 mg/kg IM or SC; has been used safely in pregnant jills, use with caution in dehydrated animals. ()

b) 0.1-0.25 mg/kg IM or SC; may cause hypotension/hypothermia ()

Acepromazine dosage for rabbits, rodents, and small mammals:

a) Rabbits: As a tranquilizer: 1 mg/kg IM, effect should begin in 10 minutes and last for 1-2 hours ()

b) Rabbits: As a premed: 0.1-0.5 mg/kg SC; 0.25-2 mg/kg IV, IM, SC 15 minutes prior to induction. No analgesia; may cause hypotension/hypothermia. ()

c) Mice, Rats, Hamsters, Guinea pigs, Chinchillas: 0.5 mg/kg IM. Do not use in Gerbils. ()

Acepromazine dosage for cattle:

a) Sedation: 0.01-0.02 mg/kg IV or 0.03-0.1 mg/kg IM ()

b) 0.05 -0.1 mg/kg IV, IM or SC ()

c) Sedative one hour prior to local anesthesia: 0.1 mg/kg IM ()

Acepromazine dosage for horses:

(Note: ARCI UCGFS Class 3 Acepromazine)

a) For mild sedation: 0.01-0.05 mg/kg IV or IM. Onset of action is about 15 minutes for IV; 30 minutes for IM ()

b) 0.044-0.088 mg/kg (2-4 mg/100 lbs. body weight) IV, IM or SC (Package Insert; PromAce — Fort Dodge)

c) 0.02-0.05 mg/kg IM or IV as a preanesthetic ()

d) Neuroleptanalgesia: 0.02 mg/kg given with buprenorphine (0.004 mg/kg IV) or xylazine (0.6 mg/kg IV) ()

e) For adjunctive treatment of laminitis (developmental phase): 0.066-0.1 mg/kg 4-6 times per day ()

Acepromazine dosage for swine:

a) 0.1-0.2 mg/kg IV, IM, or SC ()

b) 0.03-0.1 mg/kg ()

c) For brief periods of immobilization: acepromazine 0.5 mg/ kg IM followed in 30 minutes by ketamine 15 mg/kg IM. Atropine (0.044 mg/kg IM) will reduce salivation and bronchial secretions. ()

Acepromazine dosage for sheep and goats:

a) 0.05-0.1 mg/kg IM ()

Monitoring

■ Cardiac rate/rhythm/blood pressure if indicated and possible to measure

■ Degree of tranquilization

■ Male horses should be checked to make sure penis retracts and is not injured

■ Body temperature (especially if ambient temperature is very hot or cold)

Client Information

■ May discolor the urine to a pink or red-brown color; this is not abnormal

■ Acepromazine is approved for use in dogs, cats, and horses not intended for food

Chemistry / Synonyms

Acepromazine maleate (formerly acetylpromazine) is a phenothiazine derivative that occurs as a yellow, odorless, bitter tasting powder. One gram is soluble in 27 mL of water, 13 mL of alcohol, and 3 mL of chloroform.

Acepromazine Maleate may also be known as: acetylpromazine maleate, “ACE”, ACP, Aceproject, Aceprotabs, PromAce, Plegicil, Notensil, and Atravet.

Storage / Stability/Compatibility

Store protected from light. Tablets should be stored in tight containers. Acepromazine injection should be kept from freezing.

Although controlled studies have not documented the compatibility of these combinations, acepromazine has been mixed with atropine, buprenorphine, chloral hydrate, ketamine, meperidine, oxymorphone, and xylazine. Both glycopyrrolate and diazepam have been reported to be physically incompatible with phenothiazines, however, glycopyrrolate has been demonstrated to be compatible with promazine HC1 for injection.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Acepromazine Maleate for Injection: 10 mg/mL for injection in 50 mL vials; Aceproject (Butler), PromAce (Fort Dodge); generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

Acepromazine Maleate Tablets: 5, 10 & 25 mg in bottles of 100 and 500 tablets; PromAce (Fort Dodge); Aceprotabs (Butler) generic; (Rx). Approved forms available for use in dogs, cats and horses not intended for food.

When used in an extra-label manner in food animals, it is recommended to use the withdrawal periods used in Canada: Meat: 7 days; Milk: 48 hours. Contact FARAD (see appendix) for further guidance.

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

Human-Labeled Products: None

Categories
Horses

Twins

The diffuse microcotyledonary placentation of the mare makes it highly unlikely that a twin pregnancy will be carried to term. If the twin pregnancy is maintained until the latter part of gestation the placenta cannot meet the nutrient demands of the rapidly growing fetuses. Death of one or both fetuses is followed by abortion, with the characteristic avillous areas on the fetal membranes confirming the amount of placental disruption (). Twin abortions in the last few months of gestation are likely to cause a dystocia. The live birth of twin foals is extremely uncommon, and many of these neonates do not survive. The mares are prone to fetal membrane retention and may be difficult to rebreed. Thus it is not surprising that the equine breeding industry has always tried to avoid twin pregnancies. This chapter will review the management options that are currently available.

Monitoring Follicular Development And Ovulation

A high incidence of twin ovulations occurs in some breeds, such as Thoroughbreds and warmbloods, and mares that tend to double ovulate can be expected to do this repeatedly. Thus a mare with a tendency to double-ovulate should have this information noted prominently on her breeding record. Most twin pregnancies arise from such double ovulations. Owners need to appreciate that these double ovulations are generally asynchronous and may be separated by a couple of days. If a fertile stallion was used to breed the mare on the first ovulation, it is possible that viable sperm will still be present in the reproductive tract when the second oocyte arrives. This possibility must be remembered when scanning mares for pregnancy at 14 to 16 days. At that time, it is good practice to scan the ovaries for evidence of luteal tissue from a second ovulation.

In the past, one strategy that was employed when a veterinarian palpated two large (>30 mm) follicles was to wait to breed until the next cycle. This approach wasted valuable days in the breeding season, and many of these mares would repeat the same follicular process during the next cycle. An alternate approach was to hope that the second follicle would continue to develop for 10 to 12 hours after the first detected ovulation. Because the ovulated oocyte is unlikely to be viable at this time, a delayed breeding could be performed in anticipation of the second ovulation. Today the preferred strategy is to breed all eligible mares — irrespective of the number of preovulatory follicles. The widespread adoption of early ultrasonographic pregnancy examinations has permitted the focus to be placed on embryonic vesicle reduction once the presence of a twin pregnancy has been confirmed.

Manual Reduction

The increasing size of the embryonic vesicle, coupled with the increasing tone of the early pregnant uterus, tends to fix the conceptus at the base of one uterine horn by day 16. It is essential that the ultrasound scan of the uterus be thorough, with a complete examination of the length of both horns plus the uterine body as far back as the cervix. This is especially important before day 16 because the vesicle moves freely within the lumen of both horns and the uterine body. The advantage of these early scans is that if twin vesicles are detected it will be easier to manually separate them before day 16. Successful elimination of one vesicle is more likely at that time because the uterine walls are thin, and minimal pressure is required to crush a vesicle. A definite “pop” can be felt when the vesicle ruptures, but success should always be confirmed by ultrasound.

The downside to this approach is that an early embryonic vesicle can easily be confused with an endometrial cyst. The embryo itself does not become readily identifiable until the fourth week of pregnancy. Thus it is good practice to note the size and location of any cysts at the time the mare is being examined for breeding. However, it is not an uncommon occurrence that the veterinarian doing the early (14-16 days) pregnancy scan will be examining the mare for the first time. If no record of cyst size and location exists, it is virtually impossible to differentiate twin vesicles from a singleton and a cyst with a single examination. This is especially true because asynchronous ovulations are likely to result in considerable size discrepancy between the two vesicles. Under these circumstances it may be best to measure each suspect vesicle and note its location. A second scan in 1 to 2 days should note a size increase in any normally growing vesicle (~4 mm/day). Only then can a confident decision be made about attempting to “pinch” one of the growing vesicles. Unfortunately this delay may make separation of unilaterally fixed vesicles more difficult because of their ongoing growth and the increased uterine tone.

Manual reduction of bilaterally fixed vesicles requires less manipulation than with unilateral twins. It is a relatively easy procedure, and success rates exceeding 90% are not uncommon if the vesicle is crushed before day 16. If the vesicles are unilaterally fixed, the clinician should attempt to move the more proximal vesicle away towards the tip of the uterine horn. At this location the manual reduction procedure is less likely to disrupt the remaining vesicle. The vesicle can be crushed by pinching it between the thumb and fingers. Alternately, the vesicle is squeezed against the mare’s pelvis until it ruptures. If the twins can be separated before crushing, the success rate may be similar to that for reduction of bilateral twins. If the unilateral twins cannot be separated or are greater than 20 days’ gestation, the success rate is lower. The extra pressure used to eliminate a twin vesicle after fixation is the reason many clinicians will accompany reduction with antiinflammatory medications and progestin therapy. The likelihood of success improves with experience, and some clinicians develop a reputation for being especially adept at the procedure. Obviously the nature of the mare is an important factor, and those that strain excessively can make the procedure extremely difficult. If the unilateral vesicles are not detected until after day 20, manipulations can easily result in the disruption of both vesicles. The best option in these cases may be to wait and see whether natural reduction occurs.

Natural Reduction

Almost three quarters (70%) of twin embryonic vesicles become fixed unilaterally; only 30% of twin vesicles become fixed bilaterally. The advantage of this probability is that natural reduction to a single pregnancy is far more likely with unilaterally fixed vesicles. Over 80% of unilaterally fixed twins are likely to naturally reduce to a singleton, with over half of these occurring between days 16 and 20. On the other hand, the majority of bilaterally fixed vesicles will continue to develop. Late in the season these odds play an important part in any informed discussion about management options. Early in the season most veterinarians will opt to attempt reduction, knowing that if both vesicles are lost that it will still be possible to rebreed the mare. Close to the end of the season an unsuccessful attempt at reduction may preclude the mare from being rebred. If natural reduction does not occur by day 30, the advent of transvaginal reduction has opened a window for later attempts at reduction. If this fails, owners may opt to put the mare under lights and breed her early next season rather than be locked into a pattern of late foals.

Pregnancy Termination With Prostaglandin

If natural reduction does not occur, terminating the pregnancy with a prostaglandin injection is always possible. This will cause lysis of the corpora lutea that resulted from the double ovulation, and the precipitous decline in progesterone will bring the mare back into estrus. However, this treatment must be given before day 35. Once the endometrial cups form it may take repeated injections to terminate the pregnancy, and the mare is unlikely to return to estrus until the cups are sloughed. The endometrial cups originate from specialized fetal trophoblast cells. They secrete equine chorionic gonadotropin (eCG), a hormone that causes the development of accessory corpora lutea and thus augments the progesterone level in support of the early pregnancy.

Transvaginal Ultrasound-Guided Allantocentesis

Although the advent of transrectal ultrasonography has dramatically improved the ability of veterinarians to make an early diagnosis of twin pregnancies, diagnostic errors still occur. This could be due to an early pregnancy diagnosis when the second vesicle was too small to detect, incomplete examination of the entire uterus, poor image quality, or an inability of the clinician to differentiate two embryonic vesicles that are closely apposed to each other. If natural reduction does not occur or the diagnosis of twins is not confirmed until after 30 days, transvaginal aspiration of one vesicle is an option. The results are best if the procedure is performed before day 35. Although spontaneous reduction of twin pregnancies can occur even after day 40, the probability is low. Natural twin reduction is more likely to occur if an obvious size discrepancy is present between the two vesicles at this time.

If a transvaginal reduction is to be attempted, the mare should be treated with flunixin meglumine. Many clinicians will also administer oral altrenogest. Because sedation causes significant uterine relaxation, most clinicians use a lidocaine enema to reduce straining. The transvaginal aspiration technique employs a 5.0- or 7.5-MHz endovaginal curvilinear transducer. The transducer and casing should be cold-disinfected or sterilized before use. The assembled unit is then placed in a sterile transducer cover that has been filled with sterile lubricating gel. The transducer is advanced aseptically until it is seated lateral to the cervix. The clinician then grasps the pregnancy per rectum and advances a sterile 60-cm, 18-gauge spinal needle with an echogenic tip along the needle guide in the transducer casing. A dotted line on the ultrasound screen can be used to select a path for the needle entry into the embryonic vesicle. A sharp jab of the needle penetrates the vaginal wall, peritoneal lining, uterus, and ultimately the allantoic or yolk sac. A 60-ml syringe is attached to the needle, and the embryonic fluid aspirated. Aspiration should be stopped when danger of damaging the adjacent vesicle of unilateral twins arises. If a bilateral twin is being eliminated, the needle can be moved within the vesicle until all detectable fluid has been aspirated. The success rate is better for bilateral twin reductions. Death of the remaining twin is most likely to occur within 2 weeks of the procedure. Although reports are scarce, preliminary data suggest that experienced operators may achieve a live singleton birth in about one third of cases.

Transabdominal Ultrasound-Guided Fetal Cardiac Puncture

In advanced twin pregnancies, attempting reduction by a transabdominal approach is possible. Fetal intracardiac injection of potassium chloride is effective but requires accurate placement of the KC1 into the fetal heart. Best results are obtained when the pregnancy is between 115 and 130 days. At this stage experienced operators can achieve a 50% success rate. Procaine penicillin G can cause fetal death when injected into either the fetal thorax or abdomen, but the effect is not instantaneous. The advantage of the latter treatment is that it does not require precise placement of the injection into the fetal heart. Mares should be started on oral altrenogest, systemic antibiotics, and flunixin meglumine on the day of the procedure. The antibiotic coverage and antiinflammatory medication should be continued for 3 days.

A 3.0-MHz transducer can be used to image the 90- to 130-day fetus in the caudal abdomen, just cranial to the udder (Figure 5.9-2). Once the mare has been sedated, the uterus will relax, and the location of the fetuses will shift cranially. A sedative/analgesic combination that works well for this procedure is acepromazine (10 mg), xylazine (100 mg), and butorphanol (10 mg). The smallest and/or most easily accessible fetus is selected for reduction. The ventral abdomen should be surgically prepared, and local anesthetic infiltrated at the puncture site. Some clinicians are adept at a “free-hand” injection technique, whereby the fetus is injected by merely observing the ultrasound image. Others prefer to use an ultrasound transducer that is fitted with a biopsy guide. An 18-gauge, 6- to 8-inch spinal needle with stylet can be used for most fetal injections. The distance from the skin surface to the fetus determines the length of the needle that is required. Specialized needles with echogenic tips are available to provide better visualization via ultrasound. Once the location of the selected twin’s thorax is confirmed, the needle is introduced through the prepared skin, abdominal wall, and uterus. If procaine penicillin G is to be injected, the needle may puncture either the fetal thorax or abdomen. Up to 20 ml is typically injected into the fetus. Fetal death should be confirmed the following day.

Although the benefits of supplemental progestin therapy are debatable, many clinicians suggest that the mare be medicated for at least 2 weeks if the initial twin reduction has been successful. It is essential that fetal viability be checked regularly because supplemental progestin therapy may prevent elimination of the dead fetuses if both die. Most abortions will occur within 1 to 2 months after the reduction procedure. Survival of the remaining twin seems to depend somewhat on the amount of endometrial surface that was its domain before the reduction. If the operator is experienced in the technique, between 30% and 60% of cases can be expected to deliver a singleton foal, although the ultimate size and viability may be suboptimal. The eliminated twin in these cases can be seen as a mummified remnant contained within an invaginated pouch that protrudes into the allantoic space of the viable foal’s fetal membranes.

Categories
Horses

Complications Of Burns

Infection is a serious and frequent complication of burns and must be addressed at an early stage. For the most part, normal skin commensal organisms such as Streptococcus equi var. zooepidemicus, Staphylococcus aureus, and Pseudomonas aeruginosa are encountered with some complicated by other gram-negative species, such as E. coli and Clostridia spp., and yeasts can be found. Silver sulfadiazine (Silvadene) is a useful broad antibacterial that has little or no harmful effects on wound healing.

Some horses suffer from renal shutdown after sustaining a severe burn and renal function must be encouraged and repeatedly checked. Diuretics such as furosemide are often indicated but should be used with considerable care.

Smoke inhalation or internal burns can cause serious pulmonary edema and thus must be controlled. Oxygen supplied directly to the trachea or nasally may be helpful. A single intravenous dose of dexamethasone (0.5 mg/kg) may assist. Intravenous administration of dimethyl sulfoxide (DMSO) at 1 g/kg over the first 2 days may be helpful in reducing the pulmonary edema. All cases in which smoke inhalation has occurred must have systemic antibiotic therapy because the respiratory tract is particularly susceptible to serious infection after inhalation damage. Obtaining a transtracheal aspirate for culture if the chosen antibiotics do not appear to be helping is justifiable. Fungal infections pose a particularly serious threat that may be untreatable.

Cornea] and eyelid damage is particularly dangerous because of the delicate nature of the tissue and their intolerance to injury. In cases in which the face has been involved in the burn (to any extent at all) the corneas should be medicated carefully with artificial tears. In all cases the cornea should be stained with fluorescein to check for ulceration and necrotic tissue. All necrotic tissue should be gently removed with a saline-soaked cotton swab. Under no circumstances should corticosteroids or any strong chemicals such as chlorhexidine or povidone iodine be applied to the eye. Topical antibiotics (e.g., triple antibiotic or gentamicin) should be applied with atropine to control any reflex uveitis. If the eyelids are involved or are suspected to be involved, then particular care must be taken to protect the corneas with artificial tears (applied every hour), and, if necessary, a third eyelid flap can be drawn over the eye to afford sustained protection.

Healing of burn sites is reported to be slower than other types of wounds. This is possibly because the full extent of the injury is not apparent from the outset; furthermore, the damaged tissue is usually slow to separate from the healthy underlying structures. Scarring is inevitable and can be either functionally limiting (e.g., the eyelids or over joints), cosmetically unacceptable, or both. Most serious burn cases have degrees of immunosuppression, which renders them liable to infection and delayed wound healing.

Healing burn sites are often pruritic, and self-inflicted damage can be severe. Suitable sedation may be required (usually acepromazine is effective) to prevent self-inflicted trauma. Cross-tying, neck cradles, or muzzles can also be useful. These measures will require extra nursing observation.

Other complications from burns include colic (usually an impaction) or laminitis. Inappetence or failure to drink are serious potential complications and must be managed early. Fresh green grass is usually a good stimulant to appetite and also provides significant water intake. Caustic burns can result in absorption of the caustic material; thus serious systemic effects may occur.

Categories
Horses

Atopy: Diagnostic Tests

Atopic Dermatitis

Several tests can be performed if a clinician suspects a horse has atopic dermatitis. Skin biopsy shows a superficial-to-deep perivascular dermatitis with eosinophilia. This type of reaction pattern is not specific for atopy and may be seen with other types of allergies.

Other diagnostic tests, including an intradermal allergy test or a serum allergy test, can help to identify potential offending allergens but do not, however, diagnose atopy. This diagnosis must be based on a compatible history, clinical signs, and elimination of other differential diagnoses. Of the two tests, the intradermal allergy test appears to be the more sensitive and better test to identify potential sensitizing allergens in a horse. However, this test is not without its limitations, including false-positive and false-negative results.

Intradermal Allergy Test

Most clinicians sedate horses with xylazine (0.05 mg/kg IV) when they perform intradermal allergy testing. A rectangular area (30 x 15 cm) on the lateral aspect of the neck is clipped with a number 40 blade. Dots spaced approximately 2 to 5 cm apart in permanent marker identify the locations where allergens will be injected. A volume of either 0.5 or 1.0 ml of the diluted aqueous allergen is injected intradermally. Although this author prefers a volume of 1.0 ml, the exact volume does not matter as long as it is the same volume of allergen at each site. Positive and negative controls are injected at the beginning and the end of the skin test. The positive control consists of a commercially prepared solution of histamine diluted to a concentration of 1:100,000 weight to volume. Saline (0.9% NaCl solution) or sterile water serves as the negative control. The reactions are read at set time intervals; the author prefers 15 minutes, 30 minutes, 4 to 6 hours, and 24 hours after allergen injection. The reactions are graded by comparison with the controls; a 4+ reaction is similar to the positive control, whereas a 0 reaction is similar to the negative control. Size, shape, turgidity, and presence of erythema are the subjective determinations used to evaluate skin test reactions. Reactions that are greater than or equal to a 2+ reaction are considered potentially significant. Allergens that produce positive reactions at more than one reading period are probably more significant than allergens that react slightly at only one time.

The history and clinical signs should be correlated with the results of the skin tests. Certain allergens (alfalfa, corn, cornsmut, grain mill dust, grain smut, black ant, mosquitoes, Culicoides organisms, fireant, Rhizopus organisms, Penicillium organisms, sheep wool epithelium, English plantain, red mulberry, black willow, mesquite, and dock sorrel) tend to cause false-positive reactions because they may be irritating when injected intradermally. In these cases a dilution of less than 1:1000 weight to volume or several injections at several different dilutions may need to be performed. Companies that sell allergens are familiar with — and can help the veterinarian to determine — the appropriate dilutions for skin testing. These companies can also help provide a source to obtain information on pollination times for the various allergens.

False-positive reactions have been reported in non-atopic horses with chronic laminitis and musculoskeletal disease. These horses may have hypersensitive immune systems and thus tend to react more to allergens. Normally these positive reactions occur in response to the irritating allergens. If a positive reaction does not correlate well with the clinical history and physical examination, then it probably is not clinically significant.

Some drugs, especially antihistamines and corticosteroids, can interfere with skin test results. Drugs such as acepromazine that affect vasodilation can also affect the test results. If these types of drugs are not withdrawn for an appropriate length of time, false-negative skin test results will occur. This problem is usually obvious by the fact the histamine positive control does not react normally. Usually 0.1 ml of histamine creates a wheal 10 to 15 mm in diameter. Drug withdrawal times for horses should be similar to those used in small animals. Long-acting injectable steroids should not be administered for 3 months before skin testing. Oral steroids or injectable dexamethasone should not be given for at least 1 month before skin testing. Antihistamines should not be administered for a 7- to 10-day period before skin testing. If the horse’s clinical signs are severe, this drug withdrawal period can be difficult to implement, in which case it may be more advisable to skin-test at the end of allergy season. Even so, some owners refuse to take their horses off medications, and others also object to sedation and clipping of their horses. In these cases, intradermal allergy testing is not an option.

Most concentrated solutions of allergens are useable for 6 to 12 months. Prediluted allergen solutions have a shelf life of approximately 1 month. Although purchasing the concentrated solutions and making the dilutions oneself is more cost-effective, the cost of concentrated allergen solutions for most regional allergy screens is several thousand dollars. The shelf life and cost usually make intradermal skin testing cost-prohibitive for the general practitioner. For this reason and because the results of skin testing are not always easy to interpret, a board-certified veterinary dermatologist or a veterinarian who performs multiple skin tests per week should perform the skin tests.

Serum Allergy Testing

Controversy exists regarding the usefulness of the serum allergy tests in horses. Lack of repeatability of test results and sensitivity of serum allergy blood tests are problems. In a recent study, three different serum allergy tests were compared with intradermal allergy test results. These tests were an enzyme-linked immunosorbent assay (ELISA) that uses polyclonal antiequine IgE, a radioimmunosorbent assay (RIA) in which the sample was treated to minimize nonspecific IgE binding, and an ELISA test that uses the Fee receptor immunoglobulin E chain for IgE. None of the three serum allergy tests reliably detected allergen hyper-sensitivity in comparison with intradermal test results.

Despite the questionable efficacy of serum allergy testing in horses, anecdotal reports that some horses are benefited by hyposensitization based on the serum allergy blood tests exist. More studies need to be performed to adequately evaluate this situation.

Categories
Veterinary Drugs

Acepromazine

Acepromazine Maleate

(Promace)

Chemical Compound: 2-Acetyl-10-(3-dimethylaminopropyl) phenothiazine hydrogen maleate

DEA Classification: Not a controlled substance

Preparations: Generally available in 5-, 10-, 25-mg tablets and 10 mg/ml injectable forms

Clinical Pharmacology

Acepromazine is a low-potency phenothiazine neuroleptic agent that blocks postsynaptic dopamine receptors and increases the turnover rate of dopamine. Acepromazine has a depressant effect on the central nervous system (CNS) resulting in sedation, muscle relaxation, and a reduction in spontaneous activity. In addition, there are anti-cholinergic, antihistaminic, and alpha-adrenergic blocking effects.

Acepromazine, like other phenothiazine derivatives, is metabolized in the liver. Both conjugated and unconjugated metabolites are excreted in urine. Metabolites can be found in the urine of horses up to 96 hours after dosing. Horses should not be ridden within 36 hours of treatment.

Indications

Acepromazine is indicated as a preanesthetic agent, for control of intractable animals, as an antiemetic agent to control vomiting due to motion sickness in dogs and cats, and as a tranquilizer in horses.

Contraindications

Acepromazine can produce prolonged depression when given in excessive amounts or when given to animals that are sensitive to the drug. The effects of acepromazine may be additive when used in combination with other tranquilizers and will potentiate general anesthesia. Tranquilizers should be administered in smaller doses during general anesthesia and to animals that are debilitated, animals with cardiac disease, or animals with sympathetic blockage, hypovolemia, or shock. Phenothiazines should be used with caution during epidural anesthetic procedures because they may potentiate the hypotensive effects of local anesthetics. Phenothiazines should not be used prior to myelography.

Acepromazine should not be used in patients with a history of seizures and should be used with caution in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers. Studies in rodents have demonstrated the potential for embryotoxicity. Phenothiazines should not be used in patients with bone marrow depression.

Side Effects

Phenothiazines depress the reticular activating system and brain regions that control vasomotor tone, basal metabolic rate, and hormonal balance. They also affect extrapyramidal motor pathways and can produce muscle tremors and akathisia (restlessness, pacing, and agitation).

Cardiovascular side effects include hypotension, bradycardia, cardiovascular collapse, and reflex tachycardia. Hypertension is possible with chronic use. Syncope, collapse, apnea, and unconsciousness have been reported. Other side effects include hypothermia, ataxia, hyperglycemia, excessive sedation, and aggression. Paradoxical excitability has been reported in horses, cats, and dogs.

Hematological disorders have been reported in human patients taking phenothiazines, including agranulocytosis, eosinophilia, leukopenia, hemolytic anemia, thrombocytopenia, and pancytopenia.

There is anecdotal evidence that chronic use may result in exacerbation of noise-related phobias. Startle reactions to noise can increase with acepromazine use. Acepromazine is contraindicated in aggressive dogs, because it has been reported to facilitate acute aggressiveness in rare cases.

Priapism, or penile prolapse, may occur in male large animals. Acepromazine should be used with caution in stallions, as permanent paralysis of the retractor muscle is possible.

In a safety study, no adverse reactions to acepromazine occurred when it was administered to dogs at three times the upper limit of the recommended daily dosage (1.5 mg/lb). This dose caused mild depression that resolved within 24 hours after termination of dosing. The LD50 (the dose that kills half of the animals [mice] tested) is 61 mg/kg for intravenous administration and 257 mg/kg for oral administration.

Adverse Drug Interactions

Additive depressant effects can occur if acepromazine is used in combination with anesthetics, barbiturates, and narcotic agents. Concurrent use of propranolol can increase blood levels of both drugs. Concurrent use of thiazide diuretics may potentiate hypotension.

Overdose

Gradually increasing doses of up to 220 mg/kg PO were not fatal in dogs, but resulted in pulmonary edema. Hypotension can occur after rapid intravenous injection causing cardiovascular collapse. Epinephrine is contraindicated for the treatment of acute hypotension produced by phenothiazine tranquilizers because further depression of blood pressure can occur.

Overdosage of phenothiazine antipsychotics in human patients is characterized by severe CNS depression, coma, hypotension, extrapyramidal symptoms, agitation, convulsions, fever, dry mouth, ileus, and cardiac arrhythmias. Treatment is supportive and symptomatic, and it may include gastric lavage, airway support, and cardiovascular support.

Doses in Nonhuman Animals

Dosages should be individualized depending upon the degree of tranquilization required. Generally, as the weight of the animals increases, the dosage requirement in terms of milligram of medication per kilogram weight of the animal decreases. Doses that are 10 times lower than the manufacturer’s recommended dose may be effective. Arousal is most likely in the first 30 minutes after dosing. Maximal effects are generally reached in 15-60 minutes, and the duration of effect is approximately 3-7 hours. There may be large individual variation in response (Tables Doses for antipsychotics for dogs and cats and Doses of antipsychotics for horses).

Table Doses for antipsychotics for dogs and cats

Drug Canine Feline
Acepromazine 0.5-2.0 mg/kg PO q8h or prn 1.0-2.0 mg/kg PO prn
Chlorpromazine 0.8-3.3 mg/kg PO q6h 3.0-6.0 mg/kg PO
Promazine 2.0-6.0 mg/kg IM or IV q4-6h prn 2.0-4.5 mg/kg IM
Thioridizine 1.0-3.0 mg/kg PO ql2-24h
Haloperidol 0.05-2.0 mg/kg PO ql2h 0.1-1.0 mg/kg PO
Pimozide 0.03-0.3 mg/kg PO
Clozapine 1.0-7.0 mg/kg PO
Sulpiride 5.0-10.0 mg/kg PO

prn, according to need.

Table Doses of antipsychotics for horses

Drug Dose
Acepromazine 0.02-0.1 mg/kg IM
Promazine 0.4-1.0 mg/kg IV or 1.0-2.0 mg/kg PO q4-6h
Haloperidol decanoate 0.004 mg/kg IM

 

Effects Documented in Nonhuman Animals

Several incidences of idiosyncratic aggression in dogs and cats treated with acepromazine have been reported. In an incident report received by the United States Pharmacopeia Veterinary Practitioners’ Reporting Program, a German shepherd dog being treated with acepromazine following orthopedic surgery attacked and killed the other dog in the household, with no prior history of aggression. There were two incidences of aggression following acepromazine administration identified by the FDA Adverse Drug Experience Summary between 1987 and 1994. There are reports of aggressive behavior following oral and parenteral administration of acepromazine. While this is a rare side effect, the potential for serious injury should prompt practitioners to educate owners about this possibility and suggest appropriate precautions.

In horses, acepromazine can be detected in the urine for at least 25 hours after injection of 0.1 mg/kg.

Categories
Veterinary Drugs

Antipsychotics

Antipsychotics are used to treat most forms of psychosis, including schizophrenia, in humans. They do not have the same significance in animal behavior therapy and are usually most appropriately used on a short-term, intermittent basis. The first antipsychotic, chlorpromazine, was developed in 1950. Individual antipsychotic drugs show a wide range of physiological effects, resulting in tremendous variation in side effects. The most consistent pharmacological effect is an affinity for dopamine receptors. In humans, antipsychotics produce a state of relative indifference to stressful situations. In animals, antipsychotics reduce responsiveness to a variety of stimuli, exploratory behavior, and feeding behavior. Conditioned avoidance responses are lost in animals that are given antipsychotics.

Antipsychotic agents are divided into two groups based on side effect profiles (low-potency and high-potency drugs) or by structural classes (Table Classes of antipsychotic drugs). Low-potency antipsychotics have a lower affinity at D2 receptor sites, higher incidence of anticholinergic effects (sedation), stronger alpha-adrenergic blockade (cardiovascular side effects), and require larger doses (1-3 mg/kg), but have a lower incidence of extrapyramidal side effects. High-potency antipsychotics show a greater affinity for D2 receptor sites, fewer autonomic effects, less cardiac toxicity, a higher incidence of extrapyramidal signs, and are effective in smaller doses (0.5-1 mg/kg). The phenothiazine neuroleptics are antipsychotics that are commonly used in veterinary medicine for sedation and restraint.

Table Classes of antipsychotic drugs

Phenothiazine tranquilizers
High potency
Fluphenazine (Prolixin)
Low potency
Acepromazine (Promace)
Chlorpromazine (Thorazine)
Promazine (Sparine)
Thioridizine (Melleril)
Butyrophenones
Haloperidol (Haldol)
Droperidol (Innovar)
Azaperone (Stresnil, Suicalm)
Diphenylbutylpiperidines
Pimozide (Orap)
Dibenzoxazepines
Clozapine (Clozaril)
Atypical antipsychotics
Sulpiride (Sulpital)

 

Action

Antipsychotic agents block the action of dopamine, a catecholamine neurotransmitter that is synthesized from dietary tyrosine. Dopamine regulates motor activities and appetitive behaviors. Dopamine depletion is associated with behavioral quieting, depression, and extrapyramidal signs. Excess dopamine is associated with psychotic symptoms and the development of stereotypies. A large proportion of the brain’s dopamine is located in the corpus striatum and mediates the part of the extrapyramidal system concerned with coordinated motor activities. Dopaminergic neurons project to the basal ganglia and extrapyramidal neuronal system. Side effects associated with blockade of this system are called extrapyramidal responses. Dopamine is also high in some regions of the limbic system.

The nigrostriatal pathway consists of cell bodies originating in the substantia nigra and mediates motor activities. The mesolimbic pathway consists of neuronal cell bodies that originate in the ventral tegmental area, project to ventral striatum and limbic structures, and mediate appetitive behaviors. Dopamine is broken down by monoamine oxidase inside the presynaptic neuron or by catechol-O-methyltransferase outside the presynaptic neuron. There are five dopamine receptor subtypes. Traditional antipsychotics are D2 receptor antagonists and block 70-90% of D2 receptors at therapeutic doses.

Antipsychotics have a wide spectrum of physiological actions. Traditional antipsychotics have antihistaminic activity, dopamine receptor antagonism, alpha-adrenergic blockade, and muscarinic cholinergic blockade. Blockade of dopamine receptors in the basal ganglia and limbic system produces behavioral quieting, as well as depression of the reticular-activating system and brain regions that control thermoregulation, basal metabolic rate, emesis, vasomotor tone, and hormonal balance. Antipsychotics produce ataraxia: a state of decreased emotional arousal and relative indifference to stressful situations. They suppress spontaneous movements without affecting spinal and pain reflexes.

Overview of Indications

Antipsychotic agents are most often used in veterinary practice when chemical restraint is necessary. Antipsychotic agents are used for restraint or the temporary decrease of motor activity in cases of intense fear or stereotypic behavior. A complete behavioral and medical history is necessary to determine which pharmacological agents will be the most beneficial for any given case. A comprehensive treatment plan that includes behavior modification exercises and environmental modifications, along with drug therapy, has the best chance for success.

Antipsychotic agents have poor anxiolytic properties and should not be the sole treatment for any anxiety-related disorder. Therefore, while they can be useful in preventing self-injury or damage to the environment by an animal exhibiting a high-intensity fear response, they are not appropriate for long-term therapy and treatment of phobias.

Antipsychotic agents are indicated for the treatment of intense fear responses requiring heavy sedation to prevent self-injury or property damage. Sedation to the point of ataxia may be necessary to control frantic responses in storm-phobic dogs, but owners often report that their dogs still appear to be frightened.

Antipsychotic agents have also been used in game capture operations and to allow physical examination in intractable animals. Antipsychotics can also be used as antiemetics and for the treatment and prevention of motion sickness. When used as preanesthetic agents, antipsychotics may induce a state of indifference to a stressful situation.

Antipsychotic agents produce inconsistent results for the treatment of aggressive behavior, and in some cases have induced aggressive behavior in animals with no history of aggressiveness.

General Pharmacokinetics

Antipsychotic agents have a high hepatic extraction ratio. Metabolites are generally inactive compounds and excreted in the urine. Maximal effect occurs about 1 hour after administration. Duration of action ranges from 4 to 24 hours. Half-lives range from 10 to 30 hours in humans. These agents are highly lipid soluble and highly protein bound.

Contraindications, Side Effects, and Adverse Events

Significant side effects can occur with acute antipsychotic use because of decreased dopaminergic activity in the substantia nigra. Side effects may include motor deficits or Parkinsonian-like symptoms, such as difficulty initiating movements (akinesis), muscle spasms (dystonia), motor restlessness (akathisia), and increased muscle tone resulting in tremors or stiffness.

Behavior effects include indifference (ataraxia), decreased emotional reactivity, and decreased conditioned avoidance responses. Antipsychotic agents may also cause a suppression of spontaneous movements, a decrease in apomorphine-induced stereotypies, a decrease in social and exploratory behaviors, a decrease in operant responding, and a decrease in responses to non-nociceptive stimuli.

Tardive dyskinesia occurs as a result of upregulation of dopamine receptors with chronic antipsychotic use. An increase in postsynaptic receptor density due to dopamine blockade can result in the inability to control movements or torticollis, and hyperkinesis. The dopaminergic system is unique in that intermittent use of antipsychotic medications can result in up-regulation of postsynaptic receptors. Chronic side effects may occur after three months of treatment. At least 10-20% of human patients treated with antipsychotics for more than one year develop tardive dyskinesia, and the symptoms are potentially irreversible even after the medication is discontinued.

Bradycardia and transient hypotension due to alpha-adrenergic blocking effects can occur. Syncope has been reported, particularly in brachycephalic breeds. Hypertension is possible with chronic use.

Endocrine effects include an increase in serum prolactin, luteinizing hormone, follicle-stimulating hormone suppression, gynecomastia, gallactorhea, infertility, and weight gain. Parasympatholytic autonomic reactions are possible. Other side effects include lowered seizure threshold, hematological disorders (thrombocytopenia), hyperglycemia, and electrocardiographic changes. Priapism has been reported in stallions.

Antipsychotic agents should be used with caution, if at all, in patients with seizure disorders, hepatic dysfunction, renal impairment, or cardiac disease, and in young or debilitated animals, geriatric patients, pregnant females, giant breeds, greyhounds, and boxers.

Overdose

Neuroleptic malignant syndrome is a rare, but potentially fatal, complex of symptoms associated with antipsychotic use. It results in muscular rigidity, autonomic instability, hyperthermia, tachycardia, cardiac dysrhythmias, altered consciousness, coma, increased liver enzymes, creatine phosphokinase, and leukocytosis. Mortality reaches 20-30% in affected humans. Treatment includes discontinuation of the antipsychotic medication, symptomatic treatment, and medical monitoring.