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Veterinary Medicine

Dilated cardiomyopathy in the cat

The aetiology of primary dilated cardiomyopathy in the cat is unknown. Recent work has indicated a close association between dietary taurine deficiency and dilated cardiomyopathy. In the cat, taurine is an essential amino acid which is required for the conjugation of bile acids. The premise that taurine deficiency is one of the causative factors in the pathogenesis of dilated cardiomyopathy is based on the fact that many cats on taurine-deficient diets develop myocardial failure which can be reversed with taurine supplementation.

However, not all cats on taurine-depleted diets develop dilated cardiomyopathy and some which do develop cardiomyopathy fail to respond to taurine supplementation. About 38% of cats with dilated cardiomyopathy in one study failed to respond to taurine supplementation and died within the first 30 days of treatment. Hypothermia and thromboembolism were found to increase the risk of early death.

It is also known that cats on apparently adequate diets can nevertheless become taurine deficient. The minimal concentration of taurine in the diet required to prevent signs of deficiency varies with the type of diet. For example, it has been shown that much higher concentrations (2000-2500 mg taurine / kg dry matter) of taurine are required in canned diets compared to dry cat foods since heating during the canning process produces products which increase the enterohepatic loss of taurine. Low plasma taurine levels have been reported in cats fed a taurine replete but potassium depleted diet containing 0.8% ammonium chloride as a urinary acidifier suggesting a possible association between taurine and potassium balance in cats. Dietary acidification exacerbates potassium depletion in cats by decreasing gastrointestinal absorption of potassium.

It has been suggested therefore that the aetiology of feline dilated cardiomyopathy, like that of dilated cardiomyopathy in dogs, is multifactorial. There is some evidence to show that genetic factors may play a role in feline dilated cardiomyopathy. Burmese, Siamese and Abyssinian cats appear predisposed. The incidence of dilated cardiomyopathy is higher in young to middle-aged cats; the evidence for a sex predilection is equivocal).

Pathophysiology

Impairment in myocardial contractility leads to systolic dysfunction and increased end-diastolic pressures. Progressive dilatation of the ventricles results in distortion of the atrioventricular valve apparatus and mitral regurgitation which, together with the reduction in myocardial contractility, contributes to the reduction in stroke volume and decreased cardiac output.

Clinical signs of Dilated cardiomyopathy

The clinical signs may be gradual in onset and are often rather vague (lethargy, reduced activity and decreased appetite). Many of the presenting signs are similar to those of hypertrophic cardiomyopathy making differentiation between the two diseases on a clinical basis difficult. Cats which are dyspnocic may be dehydrated and hypothermic with weak femoral pulses. There may be obvious pallor or cyanosis of the mucosae with a prolonged capillary refill time. Increased respiratory crackles in association with a gallop rhythm and systolic murmur are common findings; the presence of a large volume of pleural fluid may result in muffled heart sounds. Less frequently there is also evidence of right-sided failure (jugular distension, and hepatomegaly); ascites is a rare finding.

Electrocardiography

The electrocardiographic changes do not help differentiate dilated cardiomyopathy from the hypertrophic form of the disease. Some cats remain in a relatively slow sinus rhythm. Tall R waves and wide P waves and QRS complexes may be apparent in Lead II.

Arrhythmias, especially ventricular premature complexes, have been recorded in more than 50% of cases. The mean electrical axis is often within normal limits.

Radiographic findings

Thoracic radiographs typically show evidence of generalized cardiomegaly; enlargement of the-left atrium may be particularly marked. The cardiac silhouette is often obscured by the presence of a bilateral pleural effusion. Pulmonary venous congestion and oedema may be present but these changes are usually mild and are often masked by the presence of fluid in the pleural space. The caudal vena cava is often dilated and there may be evidence of hepatomegaly.

Echocardiography

Echocardiography offers the most reliable means of differentiating dilated cardiomyopathy from hypertrophic cardiomyopathy. The interventricular septum and left ventricular free wall appear thin and poorly contractile with a marked reduction in fractional shortening. Both ventricles and the left atrium appear dilated and left ventricular end-diastolic and end-systolic internal dimensions are increased.

Laboratory findings

Normal plasma taurine levels are greater than 60 nmol l-1 ; most cats with dilated cardiomyopathy have plasma taurine concentrations less than 20 nmol l-1 and often less than 10 nmol l-1. Taurine-defielent cats with thromboembolism may have slightly higher plasma taurine concentrations due to reperfusion hyperkalaemia. Whole blood taurine has been reported to be less sensitive to acute changes in taurine intake and provides a better indication of long-term taurine intake. Whole blood taurine concentrations greater than 280 nmol l-1 are considered adequate.

Prerenal azotaemia is a common finding in cats with dilated cardiomyopathy because of reduced renal perfusion. The pleural effusion which develops with feline dilated cardiomyopathy is typically a serosanguineous modified transudate; true chylous effusions have been reported in association with right heart failure.

Angiocardiography

Non-selective angiocardiography can be used to demonstrate dilatation of all cardiac chambers. The slow circulation time in cats with dilated cardiomyopathy increases the risk of thromboembolus formation during this procedure and decompensated cases should be stabilized beforehand.

Dilated cardiomyopathy: Treatment

Cats which are severely dyspnoeic should be given oxygen, kept warm and placed in a cage. Dyspnoeic animals, particularly those with suspected pleural effusion, should be handled with care and should not be placed in dorsal or lateral recumbency for radiography. A dorsoventral radiograph taken with the animal resting in sternal recumbency is usually sufficient to confirm the presence of pleural fluid. Thoracocentesis should be attempted before a more detailed radiographic examination is performed. Other therapeutic strategics are summarized below.

Digoxin improves myocardial contractility in some but not all cats with dilated cardiomyopathy and it has been suggested that the drug may act synergistically with taurine in this respect.The liquid form of the drug is unpalatable and is generally not well tolerated. There is considerable individual variation in the way in which cats respond to digoxin. The maintenance oral dose is 0.01 mg kg-1 every 48 h for an average 3-4 kg cat which is less than one quarter of a 62.5 μg tablet every other day. Cats with dilated cardiomyopathy are more susceptible to digoxin toxicity and tend to show toxic signs when the plasma concentration of digoxin is approximately 50% of the level which would be considered toxic in a normal healthy cat. Approximately 50% of cats given 0.01 mg kg-1 body weight every 48 h show signs of toxicity.

Other positive inotropic agents such as dopamine and dobutamine must be given by constant slow intravenous infusion and are, therefore, not used as extensively. Both drugs can be given at a rate of 1-5 μg kg-1 body weight min-1 ; with dobutamine, seizures have been reported with infusion rates as low as 5 μg kg-1 min-1 in cats.

Frusemide (initially 1.0 mg kg-1 body weight intravenously twice daily; for maintenance 1-2 mg kg-1 body weight per os once or twice daily)

Mixed arteriovenous vasodilators such as captopril (3.12-6.25 mg kg-1 body weight per os twice or three times daily; this dose equates to approximately one-eighth to one quarter of a 25 mg tablet) or venodilators such as 2% nitroglycerine ointment (1/8-1/4 inch applied three times daily to the inside of the pinna) can be given although the beneficial effects of these drugs have yet to be evaluated fully in cats with dilated cardiomyopathy. They should not be given to cats with cardiogenic shock since they may potentiate the fall in cardiac output especially if used in conjunction with diuretic agents.

Animals which are severely hydrated may require intravenous or subcutaneous fluid therapy, for example 0.45% saline with 2.5% dextrose solution may help combat the effects of circulatory failure. The recommended rate of infusion is 25-35 ml kg-1 body weight day-1 given in two or three divided doses. Care should be taken so that the rate of infusion optimizes cardiac output but minimizes the risk of exacerbating pulmonary oedema or a pleural effusion.

Aspirin (25 mg kg-1 body weight every 72 h).

Taurine supplementation (250-500 mg per os twice daily) may result in a dramatic clinical improvement within 1-2 weeks when dilated cardiomyopathy is associated with taurine deficiency although cehocardiographic evidence of improved cardiac performance is usually not evident until after at least three weeks of treatment.

Sodium restricted diet.

Prognosis

The prognosis for cats which fail to resond to taurine therapy is poor. About 93% of early deaths occur within the first two weeks; few survive longer than one month. Taurine supplementation can eventually be discontinued if adequate taurine intake is provided for in the food.

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Veterinary Medicine

Balanced vasodilators

Sodium nitroprusside

Sodium nitroprusside is a potent arteriolar and venodilator drug with a similar mechanism of action to the organic nitrates, h has a very short duration of action and is administered by continuous intravenous infusion starting at an initial infusion rate of 1-5 μg kg-1 min-1. It reduces pulmonary and systemic vascular resistance decreasing ventricular filling pressure and is most useful in the management of acute, life-threatening cardiogenic pulmonary oedema. The dose can be titrated upwards to effect whilst monitoring arterial blood pressure since excessive falls in arterial blood pressure are an indication of overdosage. The effects are reversed within 1-10 min of slowing the infusion rate allowing fine control of the drug’s effects. Since delivery of the drug requires accurate control at a low rate of fluid administration, an infusion pump should be used. In dogs with severe cardiac failure resulting from poor systolic function (dilated cardiomyopathy), a drug providing positive inotropic support (for example dobutamine) is required in addition to sodium nitroprusside, otherwise the reduction in preload caused by venodilation may result in a precipitous fall in cardiac output. Intravenous infusion of sodium nitroprusside should not exceed 48 h since toxic metabolites (thiocyanate) build up in the circulation. Infusions should be stopped gradually rather than abruptly to prevent rebound increases in vascular resistance and cardiac filling pressures.

Prazosin

Prazosin is a balanced vasodilator drug which can be given orally to dogs. It is an alpha1-selective adrenoceptor antagonist which blocks excessive sympathetic stimulation of vascular alpha1-adrenoceptors without affecting the autoinhibition of noradrenaline release by presynaptic alpha2-adrenoceptors. The recommended dosage is 1 mg tid for dogs weighing less than 15 kg and 2 mg tid for dogs weighing more than 15 kg. In humans and experimental animals, although prazosin is very effective initially, with repeated dosing its effects become attenuated, possibly as the renin-angiotensin system assumes greater importance in regulating vascular tone.

Angiotensin converting enzyme inhibitors

Given the effects of angiotensin II which are central to the pathophvsiology of chronic heart failure, the effects of drugs which inhibit the formation of angiotensin II by inhibition of anglotensin converting enzyme (ACE) are predictable. They are balanced vasodilators and will enhance the excretion of sodium and water by reducing circulating levels of aldosterone and ADH; thus they have a potassium-sparing diuretic effect. Angiotensin converting enzyme is also responsible for the breakdown of the natural vasodilator, bradykinin and some of the effects of ACE inhibitors can be attributed to potentiating bradykinin. Their effects on the vasculature are less profound and slower to take effect when compared to hydralazine and nitroprusside, hence these drugs are preferred to the ACE inhibitors when dealing with cases of life-threatening pulmonary oedema due to left-sided heart failure. Indeed, clinical signs may continue to improve for several weeks in human heart failure patients on ACE inhibitors and multicentre controlled clinical trials in veterinary medicine suggest that the same is true in veterinary medicine. Small but significant effects have been demonstrated on survival time of dogs with dilated cardiomyopathy and mitral valvular heart disease treated with enalapril.

Captopril was the first ACE inhibitor to be produced. It contains a sulphydryl group which causes certain side effects which are common to sulphydryl compounds, namely alterations in taste perception, proteinuria and drug-induced blood dyscrasias. The recommended dosage is 0.5-2.0 mg kgr-1 three times daily. Oral absorption is reduced by food. Exceeding the upper limit of this dose gives no further beneficial therapeutic effect but increases the drug’s toxiciry. Angiotensin II may maintain glomerular filtration pressures in the face of poor renal perfusion by constricting the efferent arteriole more than the afferent arteriole. Removal of this protective mechanism may precipitate acute renal failure in some patients with subclinical, pre-existing renal dysfunction. Hence blood plasma urea and creatinine should be determined in animals before and after they are put on ACE inhibitors. As with other vasodilator drugs, hypotension is a possible side effect, particularly if used in combination with high doses of diuretics. In humans. ACE inhibition has been associated with a drug-induced cough.

Enalapril is an ACE inhibitor with significant advantages over captopril. It does not possess a sulphydryl group and so lacks the associated side effects mentioned above. It is a pro-drug, the active form being a metabolite, enalaprilat, formed by the liver. The onset of action is slower than captopril and its duration of effect is longer (12-14 h). Recommended dosing in dogs is 0,5-1.0 mg kg-1 every 12-24 h and in cats is 0,25 mg kg-1 every 12 h. Side effects are those associated with ACE inhibition described above for captopril.

Benazepril is an ACE inhibitor recently licensed for veterinary use. It shares many properties with enalapril, lacking a sulphydryl group and being a pro-drug. In addition, the excretion of the active metabolite from the body occurs both in the bile and the urine. This contrasts with enalapril, which is eliminated in the urine only where dose adjustment may be necessary in animals with significant impairment of renal function. The recommended dose rate of benazepril for the dog is 0.25 to 0.5 mg kg-1 orally every 24 hours. Currently, there is no authorized dose rate for cats.

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Veterinary Medicine

Positive inotropic agents

An ideal positive inotropic agent should increase the force of contraction of cardiac muscle at a given degree of end-diastolic stretch without reducing efficiency of energy use, increasing the heart rate or predisposing to cardiac arrhythmias. The drug should also lack vasoconstrictor action on peripheral blood vessels.

Drugs which enhance myocardial intracellular cyclic AMP concentration

Beta-adrenergic agonists and phosphodiesterase type III / IV inhibitors will both raise intracellular cyclic AMP and increase myocardial contractility. The synthetic catecholamine, dobutamine is the beta-adrenoceptor agonist of choice since it has selective action on beta-adrenoceptors and at dose rates which increase the force of contraction (3-7 μg kg-1 min-1), it has minimal effects on heart rate and no vasoconstrictor effects. It is used in the intensive care of severe myocardial systolic failure. It is rapidly taken up and metabolized by the tissues and has to be given by continuous intravenous infusion, the rate of which should be accurately controlled by an infusion pump. Continuous ECG monitoring is required to detect increases in heart rate and the onset of arrhythmias which are indicative of toxicity. Some studies in human medicine have suggested long-term beneficial effects even following brief dobutamine infusions. Similar studies have not been reported in veterinary medicine and the cost of the drug may be prohibitive for many patients.

The bypyridine compounds amrinone and milrinone (phosphodiesterase type III / IV inhibitors) were heralded as having great promise on their introduction, being potent positive inotropes with little effect on heart rate and possessing mild arteriolar vasodilator activity. Indeed, initial studies of the use of milrinone in dogs with systolic failure (which is orally active) proved promising. Unfortunately, no placebo-controlled trials have been performed in veterinary medicine and human studies have shown a detrimental effect of milrinone on long-term survival in patients with chronic congestive heart failure. Such findings cast serious doubt on the future of such drugs. Indeed, it has been suggested that any drug which produces its positive inotropic effects by raising cyclic AMP in the myocardium will have long-term detrimental effects in the same way as chronic exposure of the myocardium to high concentrations of catecholamines is thought to be toxic.

Cardiac glycosides

Controversy over the use of this group of drugs in the management of heart failure has been present in the literature of both human and veterinary medicine for many years, yet their popularity among clinicians survives. Most would agree that the primary indication for cardiac glycosides is in the management of supraventricular tachycardia, particularly where this co-exists with systolic myocardial dysfunction, as is often the case in dilated cardiomyopathy in dogs. The controversy surrounds their use in heart failure patients which are in normal sinus rhythm and results of large-scale controlled trials in human medicine are only beginning to be reported.

The classical actions of cardiac glycosides on the failing heart are to increase the force of contraction of the heart muscle and decrease the heart rate via a number of both central and peripheral effects which result in increased vagal tone to the heart. In addition, other reflex effects occur which inhibit both sympathetic nerve and renin-angiotensin system activity. The ability of the drugs to increase the sensitivity of cardiac and arterial baroreceptors so that they respond to lower pressures leading to a reduction in sympathetic tone may underlie these beneficial circulatory effects which are now thought to occur independently of any positive inotropic action. These effects give sound reasons for employing cardiac glycosides in heart failure patients where systolic muscle function is not affected (such as valvular heart disease) although alternative means of achieving these effects now exist (for example ACE inhibitors).

Digoxin is the only cardiac glycoside which currently is readily available for use by the veterinary practitioner. The narrow therapeutic index of glycosides means that the digoxin dosage should be accurately calculated for each animal. In dogs, less than 20 kg a dose of 0.005-0.01 mg kg-1 bid is recommended whereas dogs greater than 20 kg in weight should receive 0.22 mg m-2 bid (a total dose of 0,25 mg bid should not be exceeded). The dosages should theoretically be based on lean body weight. Dosing on a twice daily basis prevents large peaks and troughs in plasma concentration. The half-life of digoxin in the dog is reported to be 23-39 h. In the cat, a dose of 0.01 mg kg-1 every other day is recommended and a 30% reduction should be made if aspirin and frusemide are administered concurrently. Renal excretion of digoxin is an important route of elimination and reduced renal function will lead to toxicity occurring at these dose rates. Food will reduce the rate of absorption of digoxin from the gastrointestinal tract and the absorption characteristics will vary from one formulation to another. Use of digoxin can be facilitated by monitoring scrum levels of the drug which should fall between 1.0 and 2.5 ng ml-1. This therapeutic range should be achieved within three to five half-lives of starting therapy (that is within 3-5 days). Rapid digitalization by giving loading doses is rarely necessary and is associated with a higher incidence of toxicity.

Signs of digoxin toxicity (anorexia and vorniring) are due to the effects of the drug on the chemoreceptor trigger zone in the medulla. In addition, myocardial toxicity will result in cardiac arrhythmias, particularly of ventricular origin. Unfortunately, myocardial toxicity can occur without gastrointestinal signs, particularly in dogs with myocardial systolic failure. Hypokalaemia and hypomagnesaemia caused by diuretic therapy will enhance the toxicity of digoxin so blood plasma electrolyte concentrations should be monitored. Concurrent use of other drugs such as quinidine and verapamil will also increase the risk of toxicity, therefore a reduction in digoxin dosage should be made if these drugs are given in combination. In managing digoxin toxicity, electrolyte abnormalities should be corrected and ventricular arrhythmias treated with lignocaine.

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Veterinary Medicine

Supraventricutar tachydysrhythmias

Sinus tachycardia (heart rates greater than 160-180 bpm in the dog and 240 bpm in the cat respectively) can occur in response to pain> fright, fever, anaemia, circulatory shock and hyperthyroidism, all states where sympathetic tone to the heart increases and as a result, the rate of impulse generation and conduction is enhanced. Drugs such as levothyroxine and bronchodilators such as terbutaline, if given in excess, may produce sinus tachycardia as a side effect. Treatment of the underlying condition (or cessation of the offending drug) will be sufficient, in most cases, to reduce the heart rate and drug therapy is not usually necessary.

Supraventricular tachydysrhythmias develop, most commonly, in animals where there is stretch of the atria (particularly the left atrium), for example, in dogs with dilated cardiomyopathy or mitral valvular insufficiency, and in cats with hypertrophic cardiomyopathy. Some congenital defects such as mitral and tricuspid dysplasia, patent ductus arteriosus and ventricular septal defect, which lead to atrial stretch, are also associated with supraveniricular tachydysrhythmias. The larger the normal heart size of the animal, the more readily supraventricular arrhythmias (particularly atrial fibrillation) will be supported. Indeed, a recent survey has shown that in Irish wolfhounds the incidence of atrial fibrillation is about 10% in apparently healthy animals. Size, however, does not appear to be the only factor involved as the same survey found no cases of atrial fibrillation in normal Old English mastiffs.

Management of supraventricular tachydysrhythmias

Most commonly, paroxysmal or sustained atrial tachydysrhythmias (usually atrial fibrillation) are associated with animals showing signs of congestive heart failure. Management of these arrhythmias should be part of the treatment of the heart failure since an uncontrolled heart rate will lead to severe compromise of cardiac function. Digoxin is the drug of choice in the management of these cases (with the exception of re-entrant supraventricular tachycardia occurring in animals with ventricular pre-excuation syndrome, where it is contraindicated) since it is the only drug currently available which slows conduction through the AV node without reducing myocardial contractility. This is particularly important in animals with poor systolic function as is the case in dilated cardiomyopathy. In severe cases of congestive heart failure due to dilated cardiomyopathy, it may be desirable to give a more effective positive inotrope, such as dobutamine. Dobutamine, however, will tend to increase conduction through the atrioventricular node, thus accelerating the ventricular response rate in atrial fibrillation. Concurrent treatment with digoxin will tend to reduce the ventricular response rate. If possiblel slow digitalization is recommended (see earlier for dose rates). High loading doses are dangerous, particularly in dogs which are hypoxic and have poor myocardial contractility.

Digoxin will not convert atrial arrhythmias into sinus rhythm but reduces the significance of the arrhythmia by slowing the ventricular response. The ideal ventricular rate which should be aimed for in the management of atrial arrhythmias has not been determined for the dog or cat. Most cardiologists would suggest that rates in excess of 160 bpm in the dog under examination conditions are too high. Some suggest training the owners to record the heart rate at home using a stethoscope and suggest a target: rate of between 70 and 110 bpm in the dog and 80-140 bpm in the cat. Such heart rates can rarely be achieved by the use of digoxin alone. Measurement of serum digoxin levels should be made after 5 days on maintenance therapy to ensure that the therapeutic serum concentration of digoxin has been achieved but not exceeded. Additional drug therapy may then be instituted in an attempt to reduce the heart rate further

The second drug recommended for use in atrial arrhythmias is diltiazem (0.5 mg kg-1 three times daily for dogs, twice daily for cats). Diltiazem is a calcium channel blocker which has effects on both cardiac and vascular smooth muscle. Conduction of electrical impulses through the atrioventricular node relies on slow calcium channels and diltiazem slows conduction through the atrioventricular node. It has the potential to reduce cardiac muscle contractility, which partly depends on calcium entry during the cardiac action potential. Diltiazem is thought to have less of a negative inotropic effect when compared with verapamil, possibly because it also reduces afterload whereas verapamil is less effective in this respect. Both verapamil and diltiazem reduce the excretion of digoxin which may necessitate a reduction in the dose of digoxin if combined with a calcium channel blocker. Calcium channel blockers are the drugs of choice in the management of re-entrant supraventricular tachycardia in animals with ventricular pre-excitation syndrome. Conversion of atrial arrhythmias into a normal sinus rhythm has been reported following the use of calcium channel blockers (Johnson, 1984)+ The conversion is short-lived in animals with underlying cardiac disease unless therapy is maintained. The arterial vasodilator properties of diltiazem will also reduce afterload and enhance coronary blood flow during diastole.

Beta-adrenoceptor antagonists can also be used to reduce the ventricular response rate in cases of supraventricular tachydysrhythmia. Propranolol is a non-selective beta-adrenoceptor antagonist which can be used for this purpose at an oral dose rate of 0.5-1 mg kg-1 twice or three times daily. The negative inotropic effect of propranolol will be particularly marked in animals relying on sympathetic drive to compensate for poor myocardial contractility. Beta-blockers, therefore, should be used with caution in any animal with signs of congestive heart failure, particularly when poor systolic function is likely to be the underlying cause. Cardioselective beta-blockers have been produced, with the main advantage that they show less tendency, compared with propranolol, to precipitate asthmatic attacks by blocking the protective bronchodilator effect of circulating adrenaline. Dose rates are available for drugs such as atenolol and metoprolol but we currently lack experience with the use of such drugs in veterinary medicine.

It should be remembered that digoxin, calcium channel blockers and beta-blockers all decrease conduction through the atrioventricular node via different mechanisms and so will have a synergistic effect when administered together. When introducing a second drug, close monitoring of the patient is necessary to ensure that excessive reduction in the heart rate does not occur Recently, adenosine has been used in human medicine to convert unstable supraventricular tachycardia into sinus rhythm and the development of drugs with favourable pharmacokinctics which are selective for cardiac adenosine receptors may, in the future, add to the therapeutic alternatives available for the management of supraventricular tachydysrhythmias.

With atrial tachydvsrhythmias of sudden onset following surgery or trauma, where there is no sign of cardiomegaly or congestive heart failure, it may be reasonable to attempt to convert the rhythm into normal sinus rhythm. This can be attempted by the use of quinidine or diltiazem. Quinidine has antimuscarinic properties and so may increase the ventricular rate initially before converting the rhythm back into sinus rhythm. For this reason, it is recommended to digitalize the animal before attempting conversion with quinidine. When administering quinidine with digoxin, it should be remembered that quinidine displaces digoxin from skeletal muscle binding sites so raising the serum concentration of digoxin. A 50% reduction in the digoxin dose is recommended under these circumstances.

Animals (usually large breed dogs) with atrial fibrillation where the ventricular response rate is relatively slow (<150 bpm) and where there is no evidence of heart failure are likely to develop problems eventually. When they are not showing clinical signs it is reasonable to follow them and give no therapy, particularly as the optimum heart rate for a dog with atrial fibrillation has not been established.

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Drugs

Amiodarone HCL (Cordarone, Pacerone)

Class III Antiarrhythmic

Highlights Of Prescribing Information

Antidysrhythmic agent that can be used in dogs for arrhythmias associated with left ventricular dysfunction or to convert atrial fib into sinus rhythm; very limited experience warrants cautious use

May be useful in horses to convert atrial fib or V tach into sinus rhythm

Contraindicated in 2nd, 3rd degree heart block, bradyarrhythmias

In DOGS: GI disturbances (vomiting, anorexia) most likely adverse effect, but neutropenia, thrombocytopenia, bradycardia, hepatotoxicity, positive Coombs’ test reported

In HORSES: Limited use, accurate adverse effect profile to be determined; Hind limb weakness, increased bilirubin reported when used IV to convert atrial fib

Many drug interactions

What Is Amiodarone HCL Used For?

Because of its potential toxicity and lack of experience with use in canine and equine patients, amiodarone is usually used when other less toxic or commonly used drugs are ineffective. It may be useful in dogs and horses to convert atrial fib into sinus rhythm and in dogs for arrhythmias associated with left ventricular dysfunction. In horses, one horse with Ventricular tachycardia was converted into sinus rhythm using amiodarone.

As the risk of sudden death is high in Doberman pinschers exhibiting rapid, wide-complex ventricular tachycardia or syncope with recurrent VPC’s, amiodarone maybe useful when other drug therapies are ineffective.

Pharmacology/Actions

Amiodarone’s mechanism of action is not fully understood; it apparently is a potassium channel blocker that possesses unique pharmacology from other antiarrhythmic agents. It can be best classified a Class III antiarrhythmic agent that also blocks sodium and calcium channels, and beta-adrenergic receptors. Major properties include prolongation of myocardial cell action-potential duration and refractory period.

Pharmacokinetics

Amiodarone may be administered parenterally or orally. Amiodarone is widely distributed throughout the body and can accumulate in adipose tissue. Amiodarone is metabolized by the liver into the active metabolite desethylamiodarone. After oral administration of a single dose in normal dogs, amiodarone’s plasma half-life averaged 7.5 hours, but repeated dosing increased its half-life from 11 hours to 3.2 days.

In horses, amiodarone has a low oral bioavailability (range from 6-34%) and peak levels of amiodarone and desethylamiodarone occur about 7-8 hours after an oral dose. After IV administration amiodarone is rapidly distributed with a high apparent volume of distribution of 31 L/kg. In horses, amiodarone is relatively highly bound to plasma proteins (96%). Clearance was 0.35 L/kg/hr and median elimination half-lives for amiodarone and desethylamiodarone were approximately 51 and 75 hours, respectively ().

In humans, oral absorption is slow and variable, with bioavailabilities ranging from 22-86%. Elimination half-lives for amiodarone and desethylamiodarone range from 2.5-10 days after a single dose, but with chronic dosing, average 53 days and 60 days, respectively.

Before you take Amiodarone HCL

Contraindications / Precautions / Warnings

Amiodarone is considered contraindicated in patients (humans) hypersensitive to it, having severe sinus-node dysfunction with severe sinus bradycardia, 2nd or 3rd degree heart block, or bradycardial syncope.

Clinical experience in veterinary patients is limited. Consider use only when other less toxic and more commonly used drugs are ineffective.

Adverse Effects

Gastrointestinal effects (e.g., anorexia, vomiting) are apparently the most likely adverse effects seen in the limited number of canine patients treated. Hepatopathy (bilirubinemia, increased hepatic enzymes) has been reported in dogs on amiodarone. Because hepatic effects can occur before clinical signs are noted, routine serial evaluation of liver enzymes and bilirubin is recommended. Other adverse effects reported in dogs include bradycardia, neutropenia, thrombocytopenia, or positive Coombs’ test. During IV infusion, pain at injection site, and facial pruritus and hyperemia have been noted. Corneal deposits may be seen in dogs treated with amiodarone, but this affect apparently occurs less frequently in dogs than in humans.

In human patients, adverse effects are very common while on amiodarone therapy. Those that most commonly cause discontinuation of the drug include: pulmonary infiltrates or pulmonary fi-brosis (sometimes fatal), liver enzyme elevations, congestive heart failure, paroxysmal ventricular tachycardia, and thyroid dysfunction (hypo- or hyperthyroidism). An odd effect seen in some individuals is a bluish cast to their skin. Reversible corneal deposits are seen in a majority of humans treated with amiodarone.

Clinical experience in dogs is limited; the adverse effect profile of this drug in people warrants its use in veterinary patients only when other less toxic agents are ineffective and treatment is deemed necessary.

Reproductive / Nursing Safety

In laboratory animals, amiodarone has been embryotoxic at high doses and congenital thyroid abnormalities have been detected in offspring. Use during pregnancy only when the potential benefits outweigh the risks of the drug. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, hut the potential benefits from the use of the drug in pregnant women may he acceptable despite its potential risks.)

Overdosage / Acute Toxicity

Clinical overdosage experience is limited; most likely adverse effects seen are hypotension, bradycardia, cardiogenic shock, AV block, and hepatotoxicity. Treatment is supportive. Bradycardia may be managed with a pacemaker or beta-1 agonists (e.g., isoproterenol); hypotension managed with positive inotropic agents or vasopressors. Neither amiodarone nor its active metabolite are dialyzable.

How to use Amiodarone HCL

Note: Some human references state that because of the potential for drug interactions with previous drug therapies, the life-threatening nature of the arrhythmias being treated, and the unpredictability of response from amiodarone, the drug should be initially given (loaded) over several days in an inpatient setting where adequate monitoring can occur.

Amiodarone HCL dosage for dogs:

For conversion of atrial fibrillation:

a) At the time of writing (2007) one case report () and one retrospective evaluation () have been published using amiodarone to convert atrial fibrillation in dogs. Dosage recommendations are yet to be fully defined; monitor the current literature for further recommendations.

For recurrent ventricular tachycardia not controlled with other less toxic drugs:

a) 10-25 mg/kg PO twice daily for 7 days, followed by 5-7.5 mg/kg PO twice daily for 14 days, followed by 7.5 mg/kg PO once daily ()

b) For ventricular arrhythmias secondary to occult cardiomyopathy in Doberman pinschers: 10 mg/kg PO twice daily for one week and then 8 mg/kg PO once daily. For severe V-Tach, mexiletine is added at 5-8 mg/kg three times daily for one week. Once efficacy confirmed, patient weaned off mexiletine. ()

c) Amiodarone as above in “b”, but after 6 months may be reduced to 5 mg/kg once daily. ()

d) 10-20 mg/kg PO q12h ()

Amiodarone HCL dosage for horses:

For conversion of atrial fibrillation or ventricular tachycardia: a) 5 mg/kg/hr for one hour, followed by 0.83 mg/kg/hr for 23 hours and then 1.9 mg/kg/hour for the following 30 hours. In the study (A fib), infusion was discontinued when conversion occurred or when any side effects were noted. 4 of 6 horses converted from A fib; one horse from V tach. In order to increase success rate and decrease adverse effects, regimen should be further adapted based upon PK/PD studies in horses. ()

Monitoring

■ Efficacy (ECG)

■ Toxicity (GI effects; CBC, serial liver enzymes; thyroid function tests; blood pressure; pulmonary radiographs if clinical signs such as dyspnea/cough occur)

Client Information

■ Because of the “experimental” nature (relatively few canine/equine patients have received this agent) and the toxicity dangers associated with its use, clients should give informed consent before the drug is prescribed.

Chemistry / Synonyms

An iodinated benzofuran, amiodarone is unique structurally and pharmacologically from other antiarrhythmic agents. It occurs as a white to cream colored lipophilic powder having a pKa of approximately 6.6. Amiodarone 200 mg tablets each contain approximately 75 mg of iodine.

Amiodarone HCL may also be known as: amiodaroni hydrochloridum, L-3428, 51087N, or SKF-33134-A; many trade names are available.

Storage / Stability/Compatibility

Tablets should be stored in tight containers, at room temperature and protected from light. A 3-year expiration date is assigned from the date of manufacture.

Injection should be stored at room temperature and protected from light or excessive heat. While administering, light protection is not necessary. Use D5W as the IV diluent. Amiodarone is reportedly compatible with dobutamine, lidocaine, potassium chloride, procainamide, propafenone, and verapamil. Variable compatibility is reported with furosemide and quinidine gluconate.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information.

Human-Labeled Products:

Amiodarone Oral Tablets: 100 mg, 200 mg & 400 mg; Cordarone (Wyeth-Ayerst); Pacerone (Upsher Smith); generic; (Rx)

Amiodarone Concentrate for Injection (for IV Infusion): 50 mg/mL in 3 mL amps & vials; Cordarone (Wyeth-Ayerst); generic; (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

Dilated Cardiomyopathy: Acute Therapy

Treatment Goals

The treatment goals depend on the type and severity of the clinical signs. If severely dyspneic the initial goal is to make it easier for the cat to breathe by removing pleural effusion, by reducing pulmonary edema pharmacologically, or by administering oxygen. If the primary problem is a marked reduction in perfusion leading to hypothermia, the goal is to increase cardiac output, if possible, via the administration of an intravenous positive inotropic agent, such as dobutamine, and possibly the judicious use of intravenous fluid administration, especially if the cat is severely dehydrated.

Pleurocentesis

Pleurocentesis is often life saving in the severely dyspneic cat that has a large amount of pleural effusion. Thoracocentesis is described in posts.

Diuretic Therapy

Diuretic administration is the only reliable way to reduce pulmonary edema formation in a cat with severe dilated cardiomyopathy. Furosemide is used almost exclusively. The dose depends on the severity of the pulmonary edema, on whether the cat is currendy on furosemide for heart failure, and whether the situation is acute or chronic Cats in severe respiratory distress may need an initial dose as high as 2 mg/lb parenterally. Intravenous administration is preferred, but the drug should be administered intramuscularly if restraint for intravenous administration produces stress. Absorption half-life after intramuscular administration is around 5 minutes, so the entire dose is fully absorbed within 20 to 25 minutes. The duration of effect of furosemide after parenteral administration is probably 1 to 2 hours in a cat in heart failure. Consequently, another dose should be administered within that period if the cat is still in respiratory distress and is not severely dehydrated. A cat with a lesser amount of pulmonary edema and less respiratory distress needs a smaller dose of furosemide parenterally in the acute setting. Respiratory rate and character should be monitored carefully after diuretic administration with the cat in an oxygen-enriched environment.

Oxygen

Increasing the percent concentration of oxygen delivered to the alveoli is critical in cats in respiratory distress. This can be accomplished using a face mask, standard oxygen cage, a pediatric incubator, or nasal insufflation. Generally the goal is to increase fraction of inspired oxygen (FIO2) to at least 40% (normal is 21%). If the cat resists a face mask, it should not be used. When placed in a confined space, especially a small space like an incubator, it is mandatory to keep the environmental temperature and the carbon dioxide concentration within reasonable levels. Failure to do so can cause death. A canister containing sodium lime or barium hydroxide lime controls carbon dioxide level in an oxygen cage, and a refrigeration unit controls temperature. Carbon dioxide concentration is usually controlled in an incubator by maximizing the flow rate of oxygen (and therefore flushing out the carbon dioxide).

Inotropic Support

Beta-adrenergic agonists, usually dobutamine or dopamine, can be used for acute inotropic support in a cat widi severe dilated cardiomyopathy and severe heart failure. However, conscious cats have more side effects with these drugs than do dogs. They often appear agitated and may even seizure. The half-life of these drugs is around 1 minute, so stopping the drug infusion results in rapid cessation of adverse effects. The infusion rate for dobutamine and dopamine in a cat is less than that used in a dog and is generally in the range of 1 to 2.5 Mg/lb/min.

Nitroprusside

Nitroprusside is a potent dilator (i.e., smooth muscle relaxant) of systemic arterioles and systemic veins. It can only be used in cats with dilated cardiomyopathy that are not in cardiogenic shock (systolic systemic arterial blood pressure over 100 mm Hg). If systemic pressure is adequate, the drug can be used in one of two ways: (1) empirically at a dose of 2 µg/lb/min or (2) titrated using blood pressure starting at a dose of 1 ug/lb/min and increased until the systolic pressure has decreased by at least 10 to 15 mm Hg. ()

General Supportive Measures

Although dogs commonly start to drink water and eat once they are no longer in respiratory distress, cats may not. Dehydration is a common side effect of aggressive diuretic therapy, and some cats are dehydrated at presentation. Generally cats do better if they are sent home as soon as possible. However, if hospitalization is required after the edema and effusion are controlled, judicious use of fluid therapy may be needed. Electrolyte disturbances, most commonly hyponatremia, hypokalemia, and hypochloremia, are also more frequent in cats than in dogs in this acute setting. Consequendy, serum electrolyte concentrations should be monitored.

Categories
Diseases

Management of Chronic Mitral Valve Insufficiency

Ideally, therapy of chronic mitral valve insufficiency would halt the progression of the valvular degeneration. Improvement of valvular function by surgical repair or valve replacement would likewise stop further deterioration. However, no therapy is currently known to inhibit or prevent the valvular degeneration, and surgery is usually not technically, economically, or ethically possible in canine and feline patients. The management of chronic mitral valve insufficiency is therefore concerned with improving quality of life, by ameliorating the clinical signs and improving survival. This usually means that therapy is tailored for the individual patient, owner, and practitioner and often involves concurrent treatment with two or more drugs once signs of heart failure are evident. Management of chronic mitral valve insufficiency will be discussed in five groups of patients: those without overt signs of heart failure (asymptomatic), those with left mainstem bronchial compression, those with syncope, those with mild to moderate heart failure, those with recurrent heart failure, and those with severe and fulminant heart failure. Possible complications are discussed separately. It is unusual to treat cases of isolated chronic mitral valve insufficiency in cats and details of drug dosages for cats are therefore not included in this section.

Asymptomatic Disease

The stage when a patient starts to show clinical signs of chronic mitral valve insufficiency (CMVI), that is, have developed decompensated heart failure, is the end of a process started much earlier with the onset of valve leakage. The valvular leakage was compensated through a variety of mechanisms but as the leakage increases the valves eventually became incapable of preventing pulmonary capillary pressures from exceeding the threshold for pulmonary edema, and of maintaining forward cardiac output. It is likely that minor signs of reduced activity and mobility are present even before overt signs of heart failure develop. However, it is very difficult to objectively evaluate the presence of slight to moderately reduced exercise capacity in most dogs with chronic mitral valve insufficiency (CMVI), as they are often old small companion dogs, which if obese, have little, if any, demand on their exercise capacity. Furthermore, other concurrent diseases in the locomotor system or elsewhere are common and restrict exercise. Thus vague clinical signs such as slightly reduced exercise capacity in a typical dog with progressed chronic mitral valve insufficiency may or may not be attributable to chronic mitral valve insufficiency (CMVI).

This dilemma leads to the questions of when to start therapy, and if therapy before the onset of decompensated heart failure is beneficial, ineffective, or harmful. ACE-inhibitors are frequently prescribed to dogs with chronic mitral valve insufficiency before the onset on heart failure. At present, however, there is no evidence that administration of any medication to a patient with asymptomatic chronic mitral valve insufficiency has a preventive effect on development and progression of clinical signs of heart failure or improves survival. Two large placebo-controlled multicenter trials, the SVEP and the VetProof trials, have been conducted to study the effect of monotherapy of the ACE-inhibitor enalapril on the progression of clinical signs in asymptomatic chronic mitral valve insufficiency in dogs. Both failed to show a significant difference between the placebo and the treatment groups in time from onset of therapy to confirmed congestive heart failure.H’ The two trials differ in the following features: the SVEP trial included

only dogs of one breed (Cavalier King Charles spaniels) whereas the VetProof trial included a variety of breeds. The dogs in the VetProof trial were more frequently progressed cases of chronic mitral valve insufficiency than the dogs in the SVEP trial, and the SVEP trial comprised more dogs than the VetProof trial (229 versus 139 dogs). Suggested reasons for the non-significant findings in these trials include lack of activation of circulating RAAS activity in asymptomatic animals, low concentration of angiotensin II receptors in the canine mitral valve, or lack of effect of ACE-inhibitors on myocardial remodeling and progressive ventricular dilatation in mitral regurgitation (MR).

Owners of dogs with progressed asymptomatic chronic mitral valve insufficiency should be instructed about signs of developing heart failure and, in case of breeding, about the fact that the disease is significantly influenced by genetic factors. The disease may be monitored at regular intervals of 3 to 12 months if significant cardiomegaly is present. Milder cases do not warrant frequent monitoring (see Significance and Progression). Frequently asked questions from owners of dogs with asymptomatic chronic mitral valve insufficiency are if exercise should be restricted and if dietary measures should be instituted. At present there is little evidence-based information concerning the effects of exercise or diet on the progression of chronic mitral valve insufficiency in dogs. Dogs with mild chronic mitral valve insufficiency do not need any dietary or exercise restriction. However, from the pathophysiologic standpoint, strenuous exercise or diets with high sodium content should be avoided in progressed chronic mitral valve insufficiency as this may promote pulmonary edema. Furthermore, it is the authors’ experience that dogs with advanced asymptomatic chronic mitral valve insufficiency usually tolerate comparably long walks at their own pace and do better if obesity is avoided.

Patients with Left Mainstem Bronchial Compression Without Pulmonary Congestion and Edema

Severe left artial enlargement may produce coughing even in the absence of pulmonary congestion and edema by compression of the left mainstem bronchi, which may be identified on the lateral radiograph. With significant coughing, therapy is aimed at suppression of the cough reflex or reduction of the influence of the underlying cause for the compression, the left atrial enlargement. Cough suppressants such as butorphanol (0.55 to 1.1 mg/kg q6-12h PO), hydrocodone bitartrate (0.22 mg/kg q4-8h PO), or dextromethorphan (0.5 to 2 mg/kg q6-8h PO) may alleviate the coughing in some cases. Dogs with evidence of concurrent tracheal instability or chronic small airway disease may improve with a bronchodilator, or a brief course of glucocorticoids. Different xanthine derivatives, such as aminophylline (8 to 11 mg/kg q6-8h) and theophylline (Theo-Dur (sustained duration) 20 mg/kg q12h PO, Detriphylline (Choledyl) (sustained action) 25 to 30 mg/kg q12h PO), are commonly used bronchodilators, although the efficacy of these drugs varies considerably between individuals. Beta 2-receptor agonists such as terbutaline and albuterol should be used with caution in chronic mitral valve insufficiency dogs, as these drugs may produce unwanted elevation in heart rate and contractility as a consequence of myocardial beta 2-receptor stimulation. A reduction of left atrial size may be obtained either by reduction of the regurgitation or by reduction of pulmonary venous pressure. Regurgitation can be decreased by reducing aortic impedance with an arterial dilator or by contracting blood volume with a diuretic.

ACE-inhibitors or a directly acting arterial vasodilator, such as hydralazine, may reduce systemic arterial resistance. The ACE-inhibitors are substantially weaker arterial vasodilators than hydralazine. Side effects of ACE-inhibitors are infrequent, but monitoring of renal function and serum electrolytes, particularly potassium, may be indicated.

Hydralazine has been widely used in patients with chronic mitral valve insufficiency at an initial dosage of 0.5 mg/kg every 12 hours PO. The dosage is increased at daily to weekly intervals to an appropriate maintenance dose of 1 to 2 mg/kg every 12 hours PO, or until hypotension develops, detected either by blood pressure measurements or by clinical signs. Clinical hypotension is defined as a mean arterial blood pressure of less than 50 to 60 mm Hg or a systolic blood pressure below 90 mm Hg. Reflex tachycardia may develop in response to hypotension, and gastrointestinal problems are sometimes observed. In tachycardia, digoxin may be considered in order to limit the resting heart rate. As a consequence of hypotension, hydralazine may induce fluid retention and thereby is needed in the form of a diuretic. Patients that receive hydralazine should routinely be monitored, including having the owner check the heart rate at home and having renal function assessed periodically. Diuretic mono-therapy may be considered to decrease the mitral regurgitation by contracting the blood volume and thereby the left ventricular size. However, diuretics activate the renin-angiotensin-aldosterone system (RAAS), and in the long term may cause electrolyte disturbances. Accordingly, these drugs are often reserved for patients with signs of pulmonary congestion and edema or patients in which cough suppressants, glucocortocoids, and vasodilators have failed to alleviate clinical signs.

Patients with Syncopes but Without Pulmonary Congestion and Edema

With advancing chronic mitral valve insufficiency it is not uncommon that episodes of syncope develop in otherwise asymptomatic dogs (see Clinical Signs). These episodes vary in frequency from isolated to multiple events every day. In dogs with chronic mitral valve insufficiency with syncope, it is important to ascertain that the patient is actually fainting and not suffering from neurologic or metabolic disease. Furthermore, it is important to rule out the presence of congestive heart failure or a bradyarrhythmia such as third degree AV-block or a tachyarrhythmia such as atrial fibrillation. Although ventricular tachyarrhythmias do occur in dogs with advanced chronic mitral valve insufficiency (CMVI), supraventricular tachyarrhythmia is far more common. Typically, the 24-hour (Holter) ECG shows episodes of a rapid supraventricular rhythm immediately followed by a bradycardia during which the dog faints. Management of these dogs often includes digoxin to control the supraventricular tachyarrhythmia. In fact, the frequency of syncopes may often be controlled at lower doses, such as 50%, of digoxin than the recommended dose (which is 0.22 mg/m2 q12h PO).The place for beta-blockers in controlling episodes of fainting in chronic mitral valve insufficiency dogs is not clear. Reports indicate positive results of carvedilol in some dogs. However, beta-blockers may reduce myocardial performance and some chronic mitral valve insufficiency dogs do not tolerate this type of therapy.

Patients Unth Pulmonary Edema Secondary To Chronic Mitral Valve Insufficiency

Considering the pathophysiology of chronic mitral valve insufficiency (CMVI), therapy should be directed toward (1) reduction of the venous pressures to alleviate edema and effusions, (2) maintainance of adequate cardiac output to prevent signs of weakness, lethargy and prerenal azotemia, (3) reduction of the cardiac workload and regurgitation, and (4) protection of the heart from negative long-term effects of neurohormones. Cases with mild pulmonary edema may be managed on an outpatient basis with regular re-examinations. Cases with moderate to severe pulmonary edema may need intensive care, including cage-rest and sometimes oxygen supplementation.

Mild to Moderate Heart Failure

Patients with mild to moderate heart failure usually present with cough, tachypnea, and dyspnea. It is not common for an untreated dog in congestive heart failure to present initially with isolated significant ascites. Signs of congestive heart failure are usually present on thoracic radiographs as pulmonary venous congestion and increased pulmonary opacity. In some cases, it may be difficult to appreciate mild edema owing to obesity, chest conformation, underinflated lungs, or presence of age-related changes. Radiographs from the patient obtained before the onset of clinical signs may be helpful for comparison. Dogs with mild to moderate heart failure should be treated. Treatment can often be managed on an outpatient basis and should include a diuretic, such as furosemide, and an ACE-inhibitor. The place of digoxin and other positive inotropes are more controversial for treating dogs with mild to moderate heart failure (see below). The dosage of furosemide should preferably be based on clinical signs rather than radiographic findings. A patient may breathe with ease even in the presence of radiologic signs of interstitial edema, or vice versa. The usual course of treatment of a case with mild to moderate heart failure is an initial intensive treatment with furosemide (2 to 4 mg/kg q8-12h) for 2 to 3 days, after which the dosage of the diuretic is decreased to a maintenance level, such as 1 to 2 mg/kg every 12 to 48 hours or lower. More severe cases of heart failure may require higher dosages. It is important to use an appropriate dosage of diuretic to relieve clinical signs but to avoid an unnecessarily high maintenance dosage. Overzealous use of diuretics may lead to weakness, hypotension, syncope, aggravation of prerenal azotemia, and acid-base and electrolyte imbalances. Often the owner can be instructed to vary the dosage, within a fixed dose range, according to the need of the dog.

The dosage of ACE-inhibitor (e.g., enalapril, benazepril, lisinopril, ramipril, and imidapril) is usually fixed and depends on the specific ACE-inhibitor used. ACE-inhibitors are indicated in advanced chronic mitral valve insufficiency with heart failure in combination with diuretics, because dogs in large placebo-controlled clinical trials receiving an ACE-inhibitor have been shown to have less severe clinical signs of disease, better exercise tolerance, and live longer than those not receiving an ACE-inhibitor. In the dose range that is recommended for use in dogs and cats, the vasodilating actions of the drugs are not prominent and side effects associated with hypotension, such as fainting and syncope, are rare. A reason for this may be that the short-term effects of ACE-inhibitors on the circulation are dependent on the activity of the RAAS prior to administration of the drug, the higher activity the more pronounced effect of the drug. In combination with diuretics, such as furosemide, the ACE-inhibitors have synergistic effect with the diuretic by counteracting the reflectory stimulation of RAAS that occurs in diuretic therapy. Thus they decrease the tendency for fluid retention and counteract a peripheral vaso-constriction and other negative effects on the heart.

Digoxin is controversial in treating dogs with chronic mitral valve insufficiency (CMVI). There is generally a lack of scientific evidence supporting the use of digoxin. Many cardiologists, however, initiate digoxin therapy when signs of heart failure first appear. Although digoxin is a comparably weak positive inotrope and myocardial failure may not be a prominent feature of chronic mitral valve insufficiency until progressed stages, digoxin has a place in heart failure therapy by reducing reflex tachycardia, by normalizing baroreceptor activity and by reducing central sympathetic activity. Thus digoxin may be useful to reduce the heart rate, such as when hydralazine is administered, or in supraventricular tachycardia such as atrial fibrillation, and to abolish or limit the frequency of syncope (see above).

The place for a positive inotrope in the management of chronic mitral valve insufficiency is controversial, since in small dogs signs of left-side heart failure usually precede overt myocardial failure. Nevertheless, the combined calcium sensitizer/PDE III inhibitor pimobendan is now approved for veterinary use in dogs with dilated cardiomyopathy and chronic mitral valve insufficiency in many European countries, Canada, and Australia at a dose of 0.25 mg/kg every 12 hours PO. Data from controlled clinical trials of pimobendan in veterinary patients is available, although its efficacy is less documented in chronic mitral valve insufficiency than in DCM. Recendy, two controlled clinical trials (the PITCH trial and a recendy completed study from UK) were presented (unpublished), The results indicate that dogs with chronic mitral valve insufficiency receiving pimobendan as adjunct therapy to diuretics show less severe signs of heart failure and are less likely to die or reach the treatment failure end-point than those receiving an ACE-inhibitor and diuretics. Many practitioners using pimobendan have experienced a dramatic improvement in overall clinical status in some CVMI dogs, even in dogs without overt myocardial failure. The reason for this may be that pimobendan, in addition to being a positive inotrope, has arterial vasodilating properties and differs from the pure phosphodiesterase III antagonists (such as milrinone) in that it increases myocardial contractility with minimal increase in myocardial energy consumption. Furthermore, positive inotropes may theoretically reduce the mitral regurgitation by decreasing the size of the left ventricle and the mitral valve annulus through a more complete emptying of the left ventricle. However, the increased contractility may also theoretically lead to an increased systolic pressure gradient across the mitral valve and thereby generate increased regur-gitation in some cases with high peripheral vascular resistance and increase the risk for chordal rupture in affected dogs. Therefore some cardiologists initiate pimobendan as adjunct therapy to other heart failure treatment in chronic mitral valve insufficiency dogs only when echocardiographic evidence of reduced myocardial performance (increased left ventricular end-systolic dimension) is evident. Whether or not this treatment strategy is the optimal use of calcium sensitizers has not been evaluated. Some cases of chronic mitral valve insufficiency with evidence of myocardial failure have evidence of disseminated myocardial micro-infarctions, most commonly as a consequence of widespread arteriosclerosis. Some of these patients might benefit from prophylactic antithrombotic and antiplatelelet therapy, although this has not been evaluated in veterinary medicine.

The way dogs with mild to moderate heart failure are managed after initiation of therapy varies. Typically, the dog is re-examined after 1 to 2 weeks of therapy, if the dog is managed on an outpatient basis, to monitor therapeutic outcome and to establish a suitable maintenance dosage of diuretic. Should the treatment response be satisfactory after this visit, dogs may often be managed by phone contacts and re-examinations every 3 to 6 months. More severe cases may require more frequent monitoring of the disease. In areas with a seasonal climate it may be valuable to re-examine the dog before the temperature increases and instruct the owner to avoid high ambient temperatures. The use of low-sodium diets as complementary therapy in heart failure is controversial. Currently, there are no clinical studies to support that they are beneficial in managing heart failure in dogs and cats. However, dogs with symptomatic chronic mitral valve insufficiency should avoid excessive intake of sodium. Dogs that are stable on their heart failure therapy usually tolerate walks at their own pace, but strenuous exercise should be avoided.

Recurrent Heart Failure

Once an appropriate maintenance dosage of furosemide has been set in a chronic mitral valve insufficiency patient with decompensated heart failure, the dosage has to be gradually increased, often over weeks or years. Reasons for increasing the dosage often include recurrent dyspnea caused by pulmonary edema or the development of ascites. Severe ascites, which compromises respiration, may require abdominocentesis. Many chronic mitral valve insufficiency cases with less severe ascites respond to an increased dose of diuretics. Even in case of abdominocentesis, the diuretic dosage should be increased as the ascites will re-occur without changed medication after evacuation. When the dosage of furosemide has reached a level of approximately 4 to 5 mg/kg every 8 to 12 hours, sequential blocking of the nephron should be considered by adding another diuretic. The drug of choice is spironolactone (1 to 3 mg q12-24h PO) which is an aldosterone antagonist and a potassium-sparing diuretic. A thiazide, such as hydrochlorothiazide (2 to 4 mg/kg q12h PO), or triamterene (1 to 2 mg/kg q12h PO) or amiloride (0.1 to 0.3 mg/kg q24h PO), may also be considered. The documentation of triamterene and amiloride in veterinary medicine is limited.

Because the furosemide treatment precedes and is used concomitantly with these drugs, the risk of hyperkalemia is low, even when they are added to a patient that is currently treated with an ACE-inhibitor. The risk of inducing prerenal azotemia, hypotension, and acid-base and electrolyte imbalances increases with the intensity of the diuretic treatment. However, the practitioner usually has to accept some degree of these disturbances when treating a patient with heart failure and, although common, they seldom result in clinical problems. A calcium senzitizer (pimobendan) is often introduced in cases with recurrent heart failure, as echocardiographic evidence of systolic dysfunction often has developed (see above).

Severe and Life-Threatening (Fulminant) Heart Failure

The causes of acute severe heart failure are often a ruptured major tendinous chord, development of atrial fibrillation, undertreatment of existing heart failure, or intense physical activity, such as chasing birds or cats, in the presence of significant chronic mitral valve insufficiency (CMVI). Patients with severe heart failure have radio-graphic evidence of severe interstitial or alveolar edema and have significant clinical signs of heart failure at rest. They are often severely dyspneic and tachypneic and have respiratory rates in the range of 40 to 90. They may cough white or pink froth, which is edema fluid. These dogs require immediate hospitalization and aggressive treatment. However, euthanasia should also be considered, if the dog is already on high doses of diuretics and other heart failure therapy, owing to the poor long-term prognosis. It is important not to stress dogs with severe or fulminant heart failure as stress may lead to death. Therefore thoracic radiographs and other diagnostic procedures may have to wait until the dog has been stabilized.

Dogs with significant dyspnea benefit from intravenous injections of furosemide at a relatively high dose (4 to 6 mg/kg q2-6h IV). The furosemide may be administered intramuscularly should placement of an intravenous catheter not be possible. Dogs with fulminant pulmonary edema may require Herculean furosemide doses at 6 to 8 mg/kg every 2 to 8 hours IV over the first 24 hours. The exact dosage of furosemide depends not only on severity of clinical signs but also on whether or not the dog is already on oral furosemide treatment. Oxygen therapy is always beneficial in hypoxemic patients and it can preferably be administered using an oxygen cage provided that the temperature can be controlled inside the cage. Nasal inflation or a facial mask may also be used provided that the animal accepts them without struggle. Once the dog has received furosemide and oxygen treatment, an arterial vasodilator and a positive inotrope may be considered to stabilize the patient.

Commonly used vasodilating agents are hydralazine per os or intravenous nitroprusside (2.0-10 mg/kg/min). Of these two vasodilators, hydralazine is most commonly used. Owing to the severity of heart failure, dogs without previous vasodilating therapy may receive an initial dose of hydralazine of 1 to 2 mg/kg PO. Titration of the hydralazine dosage as described above is indicated in dogs already on an ACE-inhibitor and blood pressure should be monitored to detect hypotension. Nitroprusside can only be administered as an intravenous infusion, which requires an intravenous catheter. This potent vasodilator has actions on both the venous and arterial circulation. However, it is not easy to control the effects of nitroprusside and the dosage has to be titrated under careful blood-pressure monitoring to avoid serious hypotension and to ensure efficacy. These disadvantages have prevented nitroprusside from being a commonly used arterial vasodilator.

A positive inotrope such as dobutamine, or more commonly the calcium-sensitizer pimobendan (0.25 mg/kg q12h PO), may be considered to stabilize the patient with fulminant heart failure. Pimobendan may be administered together with furosemide without any arterial vasodilator as the drug has vasodilating properties itself The dose of any concurrently administered arterial vasodilator has to be adjusted. Dobutamine is administered as a constant infusion usually in combination with nitroprusside. One problem with dobutamine that limits its use is that the patient needs to be weaned from IV to oral therapy within 1 to 2 days.

Patients with severe or fulminant heart failure need frequent initial monitoring of the respiratory rate because it reflects the clinical response to the furosemide treatment. Significandy decreased respiratory rate within the first hours indicates successful therapy, whereas absence of change indicate that furosemide is required at a higher dose or more frequently. Once the respiratory rate has decreased, the dose of furosemide may be reduced according to the status of the animal and clinical judgment. Abnormal laboratory findings such as pre-renal azotemia, electrolyte imbalances and dehydration are common after high doses of furosemide. Again, these abnormalities are seldom a clinical problem and the laboratory values often tend to shift towards normal with clinical improvement and as the dog starts to eat and drink. Dehydration is usually not severe even after intensive furosemide treatment and intravenous rehydration should be performed slowly and with caution in cases where it is needed, as the volume challenge may produce pulmonary edema.

 

Categories
Drugs

Acyclovir (Zovirax)

Antiviral (Herpes)

Highlights Of Prescribing Information

Used primarily in birds for Pacheco’s disease; may be useful in cats for Herpes infection

If given rapidly IV, may be nephrotoxic

Oral use may cause GI distress

Reduce dosage with renal insufficiency

May be fetotoxic at high dosages

What Is Acyclovir Used For?

Acyclovir may be useful in treating herpes infections in a variety of avian species and in cats with corneal or conjunctival herpes infections. Its use in veterinary medicine is not well established, however, and it should be used with caution. Acyclovir has relatively mild activity against Feline Herpesvirus-1 when compared to some of the newer antiviral agents (e.g., ganciclovir, cidofovir, or penciclovir).

Acyclovir is being investigated as a treatment for equine herpes virus type-1 myeloencephalopathy in horses, but clinical efficacy has not yet been proven and the drug’s poor oral bioavailability is problematic. There continues to be interest in finding a dosing regimen that can achieve therapeutic levels and be economically viable, particularly since the drug’s use during a recent outbreak appeared to have some efficacy in reducing morbidity and mortality (not statistically proven). Also, intravenous acyclovir may be economically feasible to treat some neonatal foals.

Pharmacology/Actions

Acyclovir has antiviral activity against a variety of viruses including herpes simplex (types I and II), cytomegalovirus, Epstein-Barr, and varicella-Zoster. It is preferentially taken up by these viruses, and converted into the active triphosphate form where it inhibits viral DNA replication.

Pharmacokinetics

In dogs, acyclovir bioavailability varies with the dose. At doses of 20 mg/kg and below, bioavailability is about 80%, but declines to about 50% at 50 mg/kg. Bioavailability in horses after oral administration is very low (<4%) and oral doses of up to 20 mg/kg may not yield sufficient levels to treat equine herpes virus. Elimination half-lives in dogs, cats and horses are approximately 3 hours, 2.6 hours, and 10 hours, respectively.

In humans, acyclovir is poorly absorbed after oral administration (approx. 20%) and absorption is not significantly affected by the presence of food. It is widely distributed throughout body tissues and fluids including the brain, semen, and CSE It has low protein binding and crosses the placenta. Acyclovir is primarily hepatically metabolized and has a half-life of about 3 hours in humans. Renal disease does not significantly alter half-life unless anuria is present.

Before you take Acyclovir

Contraindications / Precautions / Warnings

Acyclovir is potentially contraindicated (assess risk vs. benefit) during dehydrated states, pre-existing renal function impairment, hypersensitivity to it or other related antivirals, neurologic deficits, or previous neurologic reactions to other cytotoxic drugs.

Adverse Effects

With parenteral therapy potential adverse effects include thrombophlebitis, acute renal failure, and ecephalopathologic changes (rare). GI disturbances may occur with either oral or parenteral therapy.

Preliminary effects noted in cats, include leukopenia and anemias, which are apparently reversible with discontinuation of therapy.

Reproductive / Nursing Safety

Acyclovir crosses the placenta, but rodent studies have not demonstrated any teratogenic effects thus far. Acyclovir crosses into maternal milk but associated adverse effects have not been noted. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Acyclovir concentrations in milk of women following oral administration have ranged from 0.6 to 4.1 times those found in plasma. These concentrations would potentially expose the breastfeeding infant to a dose of acyclovir up to 0.3 mg/kg/day. Data for animals was not located. Use caution when administering to a nursing patient.

Overdosage / Acute Toxicity

Oral overdose is unlikely to cause significant toxicity. In a review of 105 dogs ingesting acyclovir (Richardson 2000), 10 animals were considered cases of acyclovir toxicosis. Adverse effects included vomiting, anorexia, diarrhea and lethargy. One dog developed polyuria/ polydipsia and another dog developed a mildly elevated BUN and serum creatinine 24 hours after ingesting 2068 mg/kg of acyclovir. Per the APCC database, acute renal injury was reported in one dog at a dose of 250 mg/kg. Treatment consists of standard decontamination procedures and supportive therapy. Contact an animal poison control center for further information, if necessary.

There were 92 exposures to acyclovir reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases 90 were dogs with 7 showing clinical signs; the remaining 2 cases were cats that showed no clinical signs. Common findings recorded in decreasing frequency included vomiting, diarrhea, lethargy, anorexia, and crystalluria.

How to use Acyclovir

Acyclovir dosage for birds:

For treatment of Pacheco’s Disease:

a) 80 mg/kg PO q8h or 40 mg/kg q8h IM (do not use parenterally for more than 72 hours as it can cause tissue necrosis at site of injection) ()

b) 80 mg/kg in oral suspension once daily PO; mix suspension with peanut butter or add to drinking water 50 mg in 4 oz of water for 7-14 days ()

c) When birds are being individually treated: 80 mg/kg PO or IM twice daily ()

d) For prophylaxis: Exposed birds are given 25 mg/kg IM once (give IM with caution as it is very irritating), and then acyclovir is added to drinking water at 1 mg/mL and to the food at 400 mg/quart of seed for a minimum of 7 days. Quaker parrots have been treated with a gavage of acyclovir at 80 mg/ kg q8h for 7 days. ()

Acyclovir dosage for cats:

For Herpesvirus-1 infections:

a) 10-25 mg/kg PO twice daily. Never begin therapy until diagnostic evaluation is completed. Maybe toxic in cats; monitor CBC every 2- 3 weeks. ()

Acyclovir dosage for horses:

a) Although efficacy is undetermined, anecdotal use of acyclovir orally at 10 mg/kg PO 5 times daily or 20 mg/kg PO q8h may have had some efficacy in preventing or treating horses during EHV-1 outbreaks.

Monitoring

■ Renal function tests (BUN, Serum Cr) with prolonged or IV therapy

■ Cats: CBC

Chemistry / Synonyms

An antiviral agent, acyclovir (also known as ACV or acycloguanosine), occurs as a white, crystalline powder. 1.3 mg are soluble in one mL of water. Acyclovir sodium has a solubility of greater than 100 mg/mL in water. However, at a pH of 7.4 at 37°C it is practically all unionized and has a solubility of only 2.5 mg/mL in water. There is 4.2 mEq of sodium in each gram of acyclovir sodium.

Acyclovir may be known as: aciclovirum, acycloguanosine, acyclovir, BW-248U, Zovirax, Acic, Aciclobene, Aciclotyrol, Acivir, Acyrax, Cicloviral, Geavir, Geavir, Herpotern, Isavir, Nycovir, Supraviran, Viclovir, Virherpes, Viroxy, Xorox, or Zovirax.

Storage / Stability/Compatibility

Acyclovir capsules and tablets should be stored in tight, light resistant containers at room temperature. Acyclovir suspension and sodium sterile powder should be stored at room temperature.

When reconstituting acyclovir sodium do not use bacteriostatic water with parabens as precipitation may occur. The manufacturer does not recommend using bacteriostatic water for injection with benzyl alcohol because of the potential toxicity in neonates. After reconstitution with 50-100 mL of a standard electrolyte or dextrose solution, the resulting solution is stable at 25°C for 24 hours. Acyclovir is reportedly incompatible with biologic or colloidial products (e.g., blood products or protein containing solutions). It is also incompatible with dopamine HC1, dobutamine, fludarabine phosphate, foscarnet sodium, meperidine and morphine sulfate. Many other drugs have been shown to be compatible in specific situations. 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:

Acyclovir Tablets: 400 mg & 800 mg; Zovirax (GlaxoWellcome); generic; (Rx)

Acyclovir Capsules: 200 mg; Zovirax (GlaxoWellcome); generic; (Rx)

Acyclovir Suspension: 200 mg/5 mL in 473 mL; Zovirax (GlaxoWellcome); generic; (Rx)

Acyclovir Sodium Injection (for IV infusion only): 50 mg/mL (as sodium): generic; (Rx)

Acyclovir Powder for Injection: 500 mg/vial (as sodium) in 10 mL vials; 1000 mg/vial (as sodium) in 20 mL vials; 500 mg/vial Lyophilized in 10 mL vials; Zovirax (GlaxoWellcome); generic; (Rx)

Acyclovir Ointment: 5% (50 mg/g) in 15 g; Zovirax (Biovail); (Rx)

Acyclovir Cream: 5% (50 mg/g) in 2g tubes; Zovirax (Biovail); (Rx)

Categories
Diseases

Patent Ductus Arteriosus

The circulation in the fetus differs from that in the adult. In fetal animals the ductus arteriosus develops from the left sixth embryonic arch and extends from the pulmonary artery to the descending aorta, where it diverts blood from the nonfunctional fetal lungs back into the systemic circulation. Prior to birth, the ductus diverts approximately 80% to 90% of the right ventricular output back to the left side of the circulation. After parturition and the onset of breathing, pulmonary vascular resistance falls, flow in the ductus reverses, and the resulting rise in arterial oxygen tension inhibits local prostaglandin release, causing constriction of the vascular smooth muscle in the vessel wall and functional closure of the ductus arteriosus. Although the ductus may be probe patent in puppies less than 4 days of age, it usually is closed securely 7 to 10 days after birth. Persistence of a patent ductus arteriosus beyond the early neonatal period is the first or second most commonly diagnosed congenital cardiac defect in dogs. Cats are also affected but much less commonly than dogs.

Pathogenesis Failed ductal closure in dogs is characterized by distinct histologic abnormalities in the ductal wall. The normal fetal ductal wall contains a loose, branching pattern of circumferential smooth muscle throughout its length. In prenatal puppies bred to have a high probability of patent ductus arteriosus (PDA), varying portions of the ductal wall are comprised of elastic fibers rather than contractile smooth muscle fibers. According to the work of Patterson et al., increasing genetic liability to patent ductus arteriosus results in “extension of the noncontractile wall structure of the aorta to an increasing segment of the ductus arteriosus, progressively impairing its capacity to undergo physiologic closure. ” It is tempting to speculate that some defect prevents one or more of the series of processes that permits smooth muscle cells to proliferate in the wall of the ductus prior to birth. In the defect’s mildest form, the ductus closes at the pulmonary arterial end only and a blind, funnel-shaped outpouching of the ventral aspect of the aorta, called a ductus diverticulum, results. This hidden form (forme fruste) of incomplete ductal closure can be diagnosed only by angiography or necropsy, but it indicates that the dog possesses genes for this defect. Increasing genetic liability results in a tapering, funnel-shaped ductus arteriosus that remains patent after the early natal period and that allows blood to flow from the high-pressure aorta to the low-pressure pulmonary artery, thereby creating varying amounts of left-to-right shunting. The most severe but least common form is the cylindrical, nontapering ductus with persistent, postnatal pulmonary hypertension (Eisenmenger’s syndrome) and bidirectional or right-to-left shunting Based on the breeding studies of poodle-type dogs, Patterson et al. concluded that the mode of transmission of patent ductus arteriosus in dogs is most likely polygenic, but other mechanisms of inheritance are possible For additional information on the morphology and pathogenesis of patent ductus arteriosus (PDA), the reader is referred to several outstanding reviews of the subject.

Pathophysiology The direction of flow through the patent ductus arteriosus is determined by the relative resistances of the pulmonary and systemic vascular beds; in the vast majority of cases, it is directed from left to right (from the aorta to pulmonary artery). This results in a continuous cardiac murmur, increased pulmonary blood flow, and volume overloading of the left atrium and left ventricle Because of the relatively high resistance of the systemic circulation after birth, aortic blood pressure is greater than pulmonary pressure, and blood shunts continuously across the patent ductus arteriosus during both systole and diastole For a given pressure gradient, the magnitude of shunting is determined by the morphology (effective resistance) of the ductus arteriosus. In most cases the ductus is widest at the aortic end and tapers to its narrowest (flow limiting) region at the point of attachment to the pulmonary artery. Increased left ventricular stroke volume and rapid runoff of blood from the aorta to the low pressure pulmonary circulation via the patent ductus arteriosus causes increased aortic systolic and decreased aortic diastolic pressures. The resulting widened arterial pulse pressure offers a hemodynamic explanation for the bounding or hyperkinetic (waterhammer, Corrigan’s) arterial pulse detected in dogs with substantial shunts.

All vascular structures involved in the transport of the shunted blood enlarge to accommodate the extra volume flow. Increased volume flow causes dilatation of the proximal aorta and main pulmonary artery and overcirculation of the pulmonary vascular bed. Dilatation of the left atrium and eccentric hypertrophy of the left ventricle develop in proportion to the volume flow of the shunt This mechanism permits compensation for a variable period, but if the shunt is large, myocardial failure (cardiomyopathy of volume overload) develops, together with progressive elevation of left ventricular end-diastolic pressure and overt pulmonary edema. Because the left-to-right shunt occurs at the level of the great vessels, the right ventricle and atrium never handle- the shunted blood, and these structures remain normal unless pulmonary vascular resistance and pulmonary arterial pressure Increase.

In a small percentage of cases, the- lumen of the patent ductus arteriosus remains wide open after birth. The absence of a restrictive ductal orifice allows aortic pressure- to be transmitted to the pulmonary circulation, precluding the normal postnatal decline in pulmonary vascular resistance. In this circumstance the aortic and pulmonary artery pressures equilibrate, and the right ventricle remains concentrically hypertrophied after birth. In Patterson’s colony of dogs, this pattern of pulmonary hypertension and reversed (right-to-left) shunting developed within the first few weeks of life. These observations fit the usual clinical presentation of most dogs diagnosed with a reversed patent ductus arteriosus (PDA), in which the animal usually has no history of a continuous murmur and no evidence of left ventricular enlargement or a large left-to-right shunt earlier in life. Most dogs with reversed patent ductus arteriosus flow have diminished pulmonary blood flow, a normal to small left ventricle, and marked concentric hypertrophy of the right ventricle. On rare occasions, dogs with a moderate to large left-to-right shunting patent ductus arteriosus experience a gradual increase in pulmonary resistance and gradual reversal of the direction of shunting, typically at several months to several years of age. These dogs often have a history of prior left heart failure. Substantial residual left ventricular (LV) enlargement is evident on thoracic radiographs and by echocardiography. Pulmonary blood flow is reduced, but right ventricular hypertrophy is less pronounced than in dogs in which the direction of shunting is reversed at an early age. The precise pathogenesis of pulmonary hypertension is not completely understood, but anatomic descriptions of the pulmonary vasculature are similar in humans and animals. Histologic changes within small pulmonary arteries include hypertrophy of the media, thickening of the intima and reduction of lumen dimensions, and development of plexiform lesions of the vessel wall. Mast of these changes are considered to be irreversible, precluding surgical correction of the reversed PDA.

Clinical findings The clinical features of patent ductus arteriosus have been thoroughly characterized in both a breeding colony and in clinic populations. Compared with male dogs, female dogs have a substantially greater risk of developing a patent ductus arteriosus (2.49 per 1000 versus 1.45 per 1000).The Chihuahua, collie, Maltese, poodle, Pomeranian, English springer spaniel, keeshond, bichon frise, and Shedand sheepdog are most frequendy affected, although other breeds, such as the Cavalier King Charles spaniel, may also be predisposed. Many other breeds, including larger dogs, such as the German shepherd, Newfoundland, and Labrador retriever, may also be prone to patent ductus arteriosus in some regions. Although severely affected pups and kittens may appear stunted, thin, or tachypneic from left heart failure, most are reported to be asymptomatic and developing normally at the time the condition is discovered. Clinical signs are rarely recognized within the first few weeks of life, and most dogs are not diagnosed until the initial examination at 6 to 8 weeks of age.

Left-to-right shunting patent ductus arteriosus A thorough physical examination and chest radiographs usually suffice to suggest the diagnosis. Mucous membranes are pink in the absence of heart failure. The precordial impulse is often exaggerated and more diffuse than normal as a result of left ventricular enlargement. A thrill may be palpated at the heart base, and a continuous murmur is best heard in the same location. The murmur’s point of maximum intensity is located over the main pulmonary artery at the dorsocranial left heart base and may radiate cranially to the thoracic inlet and to the right base, where it is almost always softer. Often only a systolic murmur is audible over the mitral area. This murmur may simply represent radiation of the loudest portion of the continuous murmur from die heart base to this location, or it may indicate that secondary mitral regurgitation has developed as a consequence of severe left ventricular dilatation. In cats, the continuous murmur of a patent ductus arteriosus may be heard best somewhat more caudoventrally than in affected dogs. Increased LV stroke volume and rapid diastolic runoff through the patent ductus arteriosus combine to produce peripheral arterial pulses that are hyperkinetic (bounding).

Electrocardiography typically indicates left ventricular enlargement (increased R-wave voltages in leads II, III, and aVF and in the left chest leads, V2 and V4) and normal mean electrical axis. Widened P waves may also be found, indicating left atrial enlargement. Chest radiographs indicate left atrial and left ventricular enlargement and pulmonary hypervas-cularity in proportion to the magnitude of the left-to-right shunt. On the dorsoventral (DV) projection, die aortic arch, left auricle, and main pulmonary artery may be abnormally prominent. The most specific radiographic finding is the appearance of an aortic bulge (“ductus bump”) near the origin of the ductus, which is caused by abrupt narrowing of the descending aorta just caudal to the origin of the ductus. Moderate to severe LV enlargement sometimes causes the cardiac apex to shift to the right (common in cats).

The diagnosis of a patent ductus arteriosus can be confirmed by echocardiography in almost all cases. Two-dimensional and M-mode echocardiography demonstrate eccentric LV hypertrophy and dilatation of the left atrium, ascending aorta, and pulmonary artery. Reduced myocardial contractility is often observed and is reflected by reduced fractional shortening and/or increased LV end-systolic dimension and e-point to septal separation (EPSS) measurements. The ductus usually can be imaged from the left cranial parasternal window. Doppler interrogation of the pulmonary artery consistently demonstrates high-velocity continuous ductal flow directed toward the pulmonic valve. In the typical case, the peak velocity of this jet is about 4.5 to 5 m/s and occurs at end-systole. Other common echocardiographic findings include a mildly increased LV outflow velocity (1.8 to 2.3 m/s) and modest secondary mitral and pulmonary valve insufficiency. In dogs with patent ductus arteriosus (PDA), associated cardiac defects are uncommon; nonetheless, a careful echocardiographic examination is worthwhile to exclude the concurrent presence of other common congenital defects, such as subaortic stenosis. Cardiac catheterization and angiocardiography are usually not needed to confirm a diagnosis of patent ductus arteriosus and are not advised unless the Doppler echocardiographic evaluation is ambiguous or additional congenital malformations are suspected.

Patent ductus arteriosus with pulmonary hypertension (right-to-left shunting PDA) High pulmonary vascular resistance tbat causes right-to-left shunting through a patent ductus arteriosus defines the clinical syndrome commonly referred to as a reversed PDA. Right-to-left shunting is observed in a very small minority of dogs with a patent ductus arteriosus (PDA), but the prevalence of this phenomenon is probably underestimated and may be greater in dogs living at altitudes higher than 5000 feet above sea level. Obvious clinical signs are usually evident during the first year of life, but many owners do not recognize clinical signs in their pet during the first 6 to 12 months of life, and some animals are not diagnosed until 3 to 4 years of age or later. Reported signs include exertional fatigue, hindlimb weakness, shortness of breath, hyperpnea, differential cyanosis and, more rarely, seizures.

The clinical examination findings are very different from those in the more common left-to-right PDA. Right-to-left flow through a widely patent ductus arteriosus exhibits little turbulence, and the physical examination reveals either no murmur or only a soft, systolic murmur at the left base. The most common auscultatory finding is an accentuated and split second heart sound. Differential cyanosis (cyanosis of the caudal mucous membranes with pink cranial membranes) may be observed, but recognition may require examination after exercise. Differential cyanosis is caused by the location of the patent ductus arteriosus (PDA), which shunts right to left from the pulmonary artery into the descending aorta but spares the proximal branches of the aorta, which provide normal oxygen delivery to the cranial portion of the body. Perfusion of the kidneys with hypoxemic blood triggers elaboration of erythropoietin and secondary polycythemia and hyperviscosity as the packed cell volume (PCV) gradually increases to 65% or greater. Polycythemia may occur during the first year of life, but it often does not become severe until 18 to 24 months of age.

The electrocardiogram of dogs with a reversed patent ductus arteriosus almost always reveals evidence of right ventricular hypertrophy (i.e., right axis deviation and increased S-wave amplitude in leads 1, II, and III and in the left precordial chest leads V2, and V4). Thoracic radiographs indicate right heart enlargement, dilatation of the main pulmonary artery, a visible ductus bump, and variable appearance of the lobar and peripheral arteries. Echocardiography demonstrates right ventricular concentric hypertrophy and a dilated main pulmonary artery. In some cases a wide, cylindrical ductus may be imaged. Pulmonary hypertension can be verified in some cases by Doppler interrogation of tricuspid or pulmonic insufficiency jets. Contrast echocardiography, nuclear scintigraphy, oximetry, or angiography can be used to demonstrate the presence of right-to-left shunting should Doppler interrogation prove inadequate. Contrast echocardiography is performed by injecting air-agitated saline into a cephalic or saphenous vein, thereby opacifying the right heart, pulmonary artery, and descending aorta (best observed by imaging of the abdominal aorta dorsal to the bladder). Cardiac catheterization can demonstrate pulmonary artery hypertension with equilibration of right and left ventricular and aortic systolic pressures. Oximetry verifies decreased oxygen saturation distal to the entrance of the patent ductus arteriosus in the descending aorta. Right ventricular angiography demonstrates right ventricular hypertrophy and usually oudines a wide patent ductus arteriosus that appears to continue distally as the descending aorta. The lobar pulmonary arteries may appear normal, especially during the first year of life, or may show increased tortuosity. Aortic or left ventricular contrast injections permit visualization of an often extensive bronchoesophageal collateral circulation.

Natural history of patent ductus arteriosus Eyster reported that approximately 64% of dogs diagnosed with a left-to-right shunting patent ductus arteriosus die of complications within 1 year of diagnosis if the condition is not surgically corrected. Complications include left heart failure with pulmonary edema, atrial fibrillation, pulmonary hypertension secondary to left heart failure, and mitral regurgitation secondary to left ventricular dilatation. Dogs and cats with patent ductus arteriosus and more modest shunts often survive to maturity, and some live beyond 10 years of age. In humans with an unconnected patent ductus arteriosus (PDA), the gradual development of pulmonary hypertension and shunt reversal is a significant risk, but this gradual transition to right-to-left shunting is uncommon in dogs. When persistent pulmonary hypertension in the neonate leads to reversed shunting, clinical signs result from hypoxemia, polycythemia, hyperviscosity, and cardiac arrhythmias. Congestive heart failure almost never develops, but sudden death and complications from hyperviscosity are common. Animals with reversed patent ductus arteriosus often live 3 to 5 years, and some survive beyond 7 years if the PCV is kept below 65%.

Clinical management Surgical correction is recommended in virtually all young dogs and cats with a left-to-right shunting PDA. Correction may not be warranted in older pets if the shunt volume is small and cardiomegaly is minimal or absent. Consultation with a specialist may be helpful in borderline circumstances. Recommended preoperative studies include ECG and chest radiographs to help assess the severity of the shunt and to determine whether congestive heart failure is present. An echocardiogram should always be performed to verify the diagnosis and to rule out additional defects. The timing of surgery is debatable, but patent ductus arteriosus correction is typically recommended at an early age or as soon as the diagnosis is made, especially if congestive heart failure appears imminent. If pulmonary edema is found on the chest radiograph, the patient should be treated medically for heart failure (furosemide, angiotensin-converting enzyme [ACE] inhibitors) prior to surgery. Positive inotropic support should also be considered. Treatment with prostaglandin inhibitors such as indomethacin (often used in premature human infants to assist closure of a structurally normal but functionally immature PDA) is not effective in dogs and cats, most likely because of the absence of smooth muscle in the ductal wall.

Two approaches to patent ductus arteriosus correction are currently available. For many years, left thoracotomy and surgical closure, typically by ligation, was the only available treatment. Other surgical methods of repair include suture occlusion with metallic clips and surgical division. These techniques and their results have been described in detail in several reports, indicating high surgical success rates and an excellent prognosis after repair. Complications of surgical patent ductus arteriosus repair in dogs most often include hemorrhage, infection, pneumthorax, cardiac arrhythmias, cardiac arrest, and heart failure. Surgical mortality should be less than 3% in uncomplicated cases. Pre-existing congestive heart failure (CHF) dramatically increases the risk of anesthetic or operative death and the rate of serious complications, underscoring the necessity of resolving pulmonary congestion prior to surgery. Positive inotropic support provided through a dobutamine infusion should also be considered for patients in this circumstance. Most dogs experience an uneventful recovery after surgery, and overall cardiac size gradually decreases toward normal, although the heart and great vessels often retain an abnormal shape. Postoperative Doppler examination may indicate a small residual shunt, although the continuous murmur is usually absent and the clinical outcomes are good. A soft left apical systolic murmur, usually from residual secondary mitral regurgitation, is often heard for a variable period after ductus ligation. Echocardiographic LV fractional shortening declines sharply immediately after surgery as a result of diminished preload and increased afterload. Medical therapy is not usually needed if signs of heart failure were not evident pre-operatively. Medical therapies required prior to surgery for congestive heart failure are often required for several months after repair. Postoperative ductal recanalization has been reported but is uncommon, occurring in less than 2% of cases, and it most commonly is associated with infection. Postoperative fever and pulmonary infiltrates may indicate infection at the surgical site and hematogenous pneumonia. The owner should be informed of the suspected heritable nature of the defect and should be advised not to use the animal for breeding.

Less invasive alternative techniques for patent ductus arteriosus occlusion are gaining popularity. Percutaneous embolization of the ductus using expandable metal devices imbedded with thrombogenic Dacron strands can be accomplished in most small animals with a patent ductus arteriosus (PDA), avoiding the morbidity of surgical thoracotomy. The most commonly used embolization device is a helical metal coil that is delivered through a small catheter via the femoral artery or other peripheral vessel. After the device has been deployed in the ductus arteriosus, the attached Dacron feathers induce thrombus formation, thereby occluding the PDA. The purported advantages of patent ductus arteriosus coil embolization over thoracotomy and surgical ligation include lower morbidity, shorter hospitalization, and faster recovery. To date the success rate of this technique has been promising and the major complication rate has been acceptably low, consisting mainly of residual shunting and pulmonary embolization of a coil. Coils that embolize to the lungs can be ignored, pushed to a peripheral location, or removed. The authors preier to remove dislodged coils, which can be quite easily accomplished using heartworm extraction forceps or other retrieval devices. Because device retention within the patent ductus arteriosus is required for successful closure, the ideal candidates for coil occlusion should have a relatively small, funnel-shaped patent ductus arteriosus that tapers to a diameter of 2 or 3 mm at the pulmonary artery end. Occlusion of large-diameter PDAs (4 mm or greater) can be attempted by deploying multiple coils into the ductal ampulla, but coil dislodgment and residual shunting are more problematic in this circumstance. Mushroom-shaped, self-expanding, occluding stents (Amplatzer) developed for human use have been successfully used to accomplish patent ductus arteriosusclosure in dogs. Advantages of this technique include secure retention of the device in the ductus with a correspondingly low rate of dislodgment, ease of delivery through the femoral vein, and suitability for closing large-diameter PDAs with a single implant. The need for specialized equipment (i.e., coils, occluding stents, catheters, fluoroscopy) and an operator experienced in performing cardiac catheterization limits the application of transcatheter patent ductus arteriosus closure techniques to university teaching hospitals and large specialty referral centers. The historical success of the traditional patent ductus arteriosus surgery makes thoracotomy and ligation a perfectly acceptable and, in some circumstances, a preferable alternative to transcatheter closure.

Animals with reversed patent ductus arteriosus have irreversible obstructive pulmonary vascular disease. Morbidity and mortality is usually due to complications related to polycythemia and chronic hypoxemia rather than congestive heart failure. Treatment of these patients consists of exercise restriction, avoidance of stress, and maintenance of the PCV between 58% and 65% by periodic phlebotomy. Long-term management by these techniques is possible. Phlebotomy should be performed cautiously to avoid weakness or collapse, and intravascular volume may be supported during phlebotomy by administration of crystalloid solutions. Attempts to reduce the red cell volume of reversed patent ductus arteriosus cases using drug therapy (e.g., hydroxyurea) have been reported and may be an alternative to repeated phlebotomy. Activity restriction is usually advised, because exercise-induced systemic vasodilatation increases the degree of right-to-left shunting and predisposes to posterior paresis or collapse and cyanosis. Closure of reversed patent ductus arteriosus is strongly contraindicated, because it invariably leads to late operative or early postoperative acute right heart failure and death.