Rapid Irregular Rhythms

Irregular heart rhythms are common, and the ECG is important for differentiating abnormal rhythms as well as sinus arrhythmia. Pulse deficits (see p. 6) and an irregular, weak pulse with heart sounds of varying intensity and regularity may be detected on physical examination. Premature contractions interrupt ventricular filling and reduce stroke volume, sometimes to the extent that there is no ejection at all for that cycle (Fig. 4-1). Rapid atrial fibrillation (AF) and premature contractions of any origin often cause pulse deficits. Ventricular premature complexes can cause audible splitting of the heart sounds because of asynchronous ven tricular activation. Ventricular and supraventricular tachycardias and AF cause more severe hemodynamic compromise than do isolated premature contractions, especially in patients with underlying heart disease.

FIG 4-1 M-mode echocardiogram at the aortic root level in a Doberman Pinscher with atrial fibrillation and dilated cardiomyopathy. Pulse deficits and variable-intensity pulses occurred secondary to the variable (or absent) aortic valve opening caused by the arrhythmia and illustrated in this echocardiogram. The motion of two aortic valve leaflets is seen within the parallel aortic root echocardiograms. Most cycles are associated with variable and poor stroke volume and with abbreviated aortic valve opening, but there is no opening at all after the sixth electrocardiogram complex from the left (arrow). R waves are indicated by white dots.

Rapid Regular Rhythms

Rapid regular rhythms include sinus tachycardia, sustained supraventricular tachycardia (SVT), and sustained ventricular tachycardia. Sinus tachycardia is caused by high sympathetic tone or drug-induced vagal blockade. Underlying causes include anxiety, pain, fever, thyrotoxicosis, heart failure, hypotension, shock, the ingestion of stimulants or toxins (e.g., chocolate, caffeine), or drugs (e.g., catecholamines, anticholinergics, theophylline, and related agents). The heart rate in dogs and cats with sinus tachycardia is usually <300 beats/min, although it can be higher in those with thyrotoxicosis or in those that have ingested exogenous stimulants or drugs (particularly cats). Alleviation of the underlying cause and intravenous (IV) administration of fluids to reverse hypotension (in animals without edema) should cause the sympathetic tone and sinus rate to decrease.

SVT of varying causes can be difficult to differentiate from sinus tachycardia. The heart rate in patients with SVT is often >300 beats/min, but it is rare for the sinus rate to be this rapid. Patients with SVTs, such as sinus tachycardia, usually have a normal QRS configuration (narrow and upright in lead II). However, if an intraventricular conduction disturbance is present, SVT may resemble ventricular tachycardia. A vagal maneuver can be useful in differentiating among narrow QRS complex tachycardias.

Sustained, rapid arrhythmias lead to decrease in cardiac output, arterial blood pressure, and coronary perfusion. CHF eventually may result. Signs of poor cardiac output and hypotension include weakness, depression, pallor, prolonged capillary refill time, exercise intolerance, syncope, dyspnea, prerenal azotemia, worsening rhythm disturbances, and sometimes altered mentation, seizure activity, and sudden death.

Supraventricular Tachyarrhythmias

Occasional premature beats do not require specific therapy. Factors that predispose to these arrhythmias should be minimized as much as possible (e.g., discontinue or reduce dosage of suspected drugs, manage heart failure if present, and treat metabolic or endocrine abnormalities).

Oral therapy for frequent supraventricular premature beats and paroxysmal tachycardia.

Initial oral therapy for frequent atrial premature complexes (APCs) or paroxysmal SVT usually involves either digoxin, diltiazem, a β-blocker, or a combination of these. Digoxin (see Table 3-3) is the initial oral drug of choice in dogs with heart failure and cats with dilated cardiomyopathy (Fig. 4-2). A β-blocker or the calcium entry blocker diltiazem may be added to the regimen if the arrhythmia is not controlled with digoxin, along with other therapy (including an ACE inhibitor) indicated for heart failure. Cats with hypertrophic cardiomyopathy or hyperthyroidism are usually treated with a β-blocker such as atenolol, although diltiazem is an alternative. Refractory intermittent supraventricular tachyarrhythmias may respond to amiodarone, sotalol, procainamide, quinidine, or a class IC agent.

FIG 4-2 A therapeutic approach to supraventricular tachyarrhythmias. See Table 4-2 for drug doses and text for more information. APCs, Atrial premature contractions; BP, blood pressure; CHF, congestive heart failure; HCM, hypertrophic cardiomyopathy; HF, heart failure or myocardial dysfunction; SVT, supraventricular tachycardia.

Ventricular Tachyarrhythmias

Occasional VPCs in an otherwise asymptomatic animal should not be treated. Moderately frequent single VPCs of uniform configuration may not require antiarrhythmic drug treatment either, especially if underlying heart function is normal. Nevertheless, guidelines as to whether, when, and how best to treat intermittent ventricular tachyarrhythmias remain undefined. Besides being expensive, antiarrhythmic drugs can have serious adverse effects, can provoke additional arrhythmias (proarrhythmic effects), and may not be efficacious. Pretreatment and posttreatment 24- to 48-hour ambulatory ECG recordings showing at least a 70% to 80% reduction in arrhythmia frequency provide the best indicator of drug arrhythmia-suppression efficacy. Intermittent ECG recordings cannot truly differentiate between drug effect (or lack thereof) and the spontaneous, marked variability of arrhythmia frequency that occurs in any individual. However, in-hospital ECG recordings of 15 seconds to several minutes in duration are often the most practical attempt to monitor arrhythmias.

Several factors influence the decision to use ventricular antiarrhythmic drug therapy. These factors include the nature of the animal’s underlying disease, the perceived severity of the arrhythmia, and the presence or absence of hemodynamic compromise. Diseases such as dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy in Boxers, hypertrophic cardiomyopathy, and subaortic stenosis, among others, are frequently associated with sudden death from arrhythmias. Therefore ventricular antiarrhythmic therapy would appear most urgent in animals with these diseases. However, the efficacy of a particular therapy to prolong survival as well as suppress the arrhythmia is difficult to accurately assess. Traditional guidelines for instituting ventricular antiarrhythmic therapy have been based on frequency, prematurity, and variability of the QRS configuration of the arrhythmia. Characteristics thought to imply increased electrical instability include rapid paroxysmal or sustained ventricular tachycardia (e.g., >130 beats/min), multiform (polymorphic) VPC configuration, or close coupling of VPCs to preceding complexes (R-on-T phenomenon). However, clear evidence that these guidelines predict greater risk of sudden death in all patients is lacking. It is probably more important to consider the animal’s underlying heart disease and whether the arrhythmia is causing signs of hypotension or low cardiac output. Animals that are hemodynamically unstable or have a disease associated with sudden cardiac death are treated earlier and more aggressively.

Acute therapy for ventricular tachycardia.

Sustained ventricular tachycardia is treated aggressively because it can result in marked decreases in arterial blood pressure, especially at faster rates. Lidocaine (IV) is usually the first-choice drug for controlling serious ventricular tachyarrhythmias in hospitalized dogs. It is effective against arrhythmias of several underlying mechanisms and has minimal adverse hemodynamic effects. Because the effects of IV boluses last only about 10 to 15 minutes, a constant rate infusion (CRI) is warranted if the drug is effective. Small supplemental IV boluses can be given in addition to the CRI to maintain therapeutic drug concentrations until a steady state is achieved. IV infusion can be continued for several days, if needed. If lidocaine is ineffective after maximal recommended doses, several other strategies can be tried (Fig. 4-3).

FIG 4-3 A therapeutic approach to ventricular tachyarrhythmias. See Table 4-2 for drug doses and text for more information. CRI, Constant-rate infusion; Dx, diagnosis; ECG, electrocardiogram.

IV amiodarone or oral mexiletine or sotalol can be more effective in some cases. With IV amiodarone, slow injection of conservative doses and blood pressure monitoring are recommended because marked hypotension can occur. Alternatively, procainamide (given intravenously, intramuscularly, or orally) or quinidine (given intramuscularly or orally) can be tried next. Effects of a single IM or oral loading dose of either drug should occur within 2 hours. If this is effective, lower doses can be given every 4 to 6 hours intramuscularly or orally. If ineffective, the dose can be increased or another antiarrhythmic drug chosen. Quinidine is not given intravenously because of its hypotensive effects. This drug is also not recommended in patients on digoxin or that have prolonged QT intervals. If the arrhythmia has not been controlled, a β-blocker can be added.

Cats with frequent ventricular tachyarrhythmias are usually given a β-blocker first. Alternatively, low doses of lidocaine can be administered. However, cats, especially if not anesthetized, can be quite sensitive to the neurotoxic effects of this drug. Procainamide or sotalol can also be used.

Digoxin is not used specifically for treating ventricular tachyarrhythmias, although it may be indicated for patients with concurrent heart failure and supraventricular arrhythmias. Digoxin can also predispose to the development of ventricular arrhythmias. Another antiarrhythmic drug may be necessary in animals with preexisting frequent or repetitive VPCs. Phenytoin is used only in dogs for digitalis-induced ventricular tachyarrhythmias that are refractory to lidocaine. Ancillary KCl supplementation (if serum K⁺ ≤4 mEq/L) with or without MgSO₄ can increase antiarrhythmic efficacy.

Close ECG monitoring and further diagnostic testing should follow initial therapy. Total suppression of persistent ventricular tachyarrhythmias is not expected. The patient’s clinical status, the underlying disease(s), the success of the drug in suppressing the arrhythmia, and the drug dosage (e.g., whether it could be increased) all influence the decision whether to continue or discontinue current treatment or to use a different drug. Clinical status and results of diagnostic testing also guide decisions about chronic oral therapy.

If the ventricular tachyarrhythmia appears refractory to initial treatment attempts, one or more of the following considerations may be helpful:

1. Reevaluate the ECG—could the rhythm have been incorrectly diagnosed initially? For example, SVT with an intraventricular conduction disturbance can mimic ventricular tachycardia. In such cases, IV diltiazem is usually more effective than lidocaine.

2. Reevaluate the serum K⁺ (and Mg⁺⁺) concentration. Hypokalemia reduces the efficacy of class I antiarrhythmic drugs (e.g., lidocaine, procainamide, quinidine) and can predispose to the development of arrhythmias. If the serum K⁺ concentration is <3 mEq/L, KCl can be infused at 0.5 mEq/kg/hr; for serum K⁺ between 3 to 3.5 mEq/L, KCl can be infused at 0.25 mEq/kg/hr. A serum K⁺ concentration in the high normal range is the goal. If the serum Mg⁺⁺ concentration is <1.0 mg/dl, MgSO₄ or MgCl₂, diluted in D₅W, can be administered at 0.75 to 1.0 mEq/kg/day by CRI.

3. Maximize the dose of the conventional antiarrhythmic drug having the greatest effect.

4. Try amiodarone (IV), sotalol (oral), or a β-blocker in conjunction with a class I drug (e.g., propranolol, esmolol, or atenolol with procainamide or lidocaine) or a class IA drug with a IB drug (e.g., procainamide with lidocaine or mexiletine).

5. Consider the possibility that the drug therapy is exacerbating the rhythm disturbance (a proarrhythmic effect). Polymorphous ventricular tachycardia (torsades de pointes) has been associated with quinidine, procainamide, and other drug toxicities.

6. MgSO₄ may be effective in animals with ventricular tachyarrhythmias associated with digoxin toxicity or with suspected polymorphous ventricular tachycardia (torsades de pointes). A slowly administered IV bolus of 25 to 40 mg/kg, diluted in D₅W, followed by an infusion of the same dose over 12 to 24 hours, has been suggested. Given that MgSO₄ contains 8.13 mEq magnesium per gram, a similar magnesium dose is provided by calculating 0.15 to 0.3 mEq/kg.

7. If the animal is tolerating the arrhythmia well, continue supportive care, correct other abnormalities as possible, and continue cardiovascular monitoring alone or with the most effective antiarrhythmic drug.

8. Direct current (DC) cardioversion or ventricular pacing may be available at a referral center; ECG-synchronized equipment and anesthesia or sedation are required. High-energy, nonsynchronized shock (defibrillation) can be used for rapid polymorphic ventricular tachycardia or flutter degenerating into fibrillation.

Atrial Fibrillation

AF most often develops when there is marked atrial enlargement. It is a serious arrhythmia, especially when the ventricular response rate is high. Predisposing conditions include dilated cardiomyopathy, chronic degenerative AV valve disease, congenital malformations that cause atrial enlargement, and hypertrophic or restrictive cardiomyopathy in cats. Clinical heart failure is common in these animals. AF is characterized by an irregular and usually rapid ventricular response rate. When little time is available for ventricular filling, stroke volume is compromised. Furthermore, atrial contraction (the “atrial kick”), which is especially important to ventricular filling at faster heart rates, is lost. Cardiac output tends to decrease considerably when AF develops; poor myocardial function exacerbates this decrease.

Long-lasting conversion to sinus rhythm is rare in the face of marked underlying cardiac disease, even after successful electrical cardioversion. Therefore treatment in most cases is directed at reducing the ventricular response rate by slowing AV conduction (Fig. 4-4). A slower heart rate allows more time for ventricular filling and lessens the relative importance of atrial contraction. In-hospital heart rates <150 (or 180 in cats) beats/min are desirable. Heart rate should be documented by ECG; counting the ventricular rate by auscultation or palpation is often highly inaccurate. Resting heart rate at home, which can be monitored by the owner, is a better indicator of drug effectiveness. Heart rates of 70 to 120 beats/min in dogs and 80 to 140 beats/min in cats are probably acceptable.

FIG 4-4 A therapeutic approach to atrial fibrillation. See Table 4-2 for drug doses and text for more information. AF, atrial fibrillation; CHF, congestive heart failure; HCM, hypertrophic cardiomyopathy; HR, heart rate.

Lone atrial fibrillation

AF sometimes develops in large or giant-breed dogs without cardiomegaly or other evidence of structural heart disease. This can occur transiently, usually in association with trauma or surgery. AF with a slow ventricular response rate can also be an incidental finding in such dogs. This is known as “lone AF”. Acute AF without signs of heart disease or failure may convert to sinus rhythm spontaneously or in response to drug therapy, such as with diltiazem (e.g. PO for ∼3 days), amiodarone, or possibly sotalol or other Class III or IC agents. Acute onset AF associated with high vagal tone may convert with IV lidocaine. Quinidine PO or IM has been used for acute AF conversion in large dogs without signs of heart disease; but adverse effects can include increased ventricular response rate from the drug’s vagolytic effects, ataxia, and most seriously, seizures or polymorphic ventricular tachycardia. If effective, the drug is discontinued after sinus rhythm is achieved. Dogs that do not convert to sinus rhythm are either given digoxin or continued on diltiazem for rate control. Alternatively, if the ventricular rate is consistently low at rest, dogs can be monitored periodically without therapy; but rapid heart rates still are likely with exercise or excitement.

Sinus Bradycardia

Slow sinus rhythm (or arrhythmia) can be a normal finding, especially in athletic dogs. Sinus bradycardia has also been associated with the administration of various drugs (e.g., xylazine, thorazine tranquilizers, some anesthetic agents, medetomidine, digoxin, calcium entry blockers, β-blockers, parasympathomimetic drugs), trauma or diseases of the central nervous system, organic disease of the sinus node, hypothermia, hyperkalemia, and hypothyroidism, among other disorders. Conditions that increase vagal tone (e.g., respiratory or gastrointestinal tract disease or a mass involving the vagosympathetic trunk) may induce sinus bradycardia. Chronic pulmonary disease often is associated with pronounced respiratory sinus arrhythmia.

In most cases of sinus bradycardia, the heart rate increases in response to exercise or atropine administration, and no clinical signs are associated with the slow heart rate. Symptomatic dogs usually have a heart rate slower than 50 beats/min and/or pronounced underlying disease. Because sinus bradycardia and sinus bradyarrhythmia are extremely rare in cats, a search for underlying cardiac or systemic disease (e.g., hyperkalemia) is warranted in any cat with a slow heart rate.

When sinus bradycardia is associated with signs of weakness, exercise intolerance, syncope, or worsening underlying disease, an anticholinergic (or adrenergic) agent is given (Fig. 4-5). If sinus bradycardia is the result of a drug effect, discontinuation, dosage reduction, or other therapy should be used, as appropriate (e.g., reversal of anesthesia or medetomidine, calcium salts for calcium entry blocker overdose, dopamine or atropine for β-blocker toxicity). If there is inadequate increase in heart rate with medical therapy, temporary or permanent pacing is indicated (see Suggested Readings).

FIG 4-5 A therapeutic approach to managing symptomatic bradyarrhythmias. See Box 3-1 and Table 4-2 and text for more information.

Sick Sinus Syndrome

Sick sinus syndrome is a condition of erratic sinoatrial function characterized by episodic weakness, syncope, and Stokes-Adams seizures. Older female Miniature Schnauzers and West Highland White Terriers are commonly affected in different regions, but the syndrome is also seen in Dachshunds, Cocker Spaniels, Pugs, and mixed-breed dogs. Affected dogs have episodes of marked sinus bradycardia with sinus arrest (or sinoatrial block). Sick sinus syndrome is extremely rare in cats.

Abnormalities of the AV conduction system may coexist, causing the activity of subsidiary pacemakers to be depressed and leading to prolonged periods of asystole. Some affected dogs also have paroxysmal SVTs, prompting the name bradycardia-tachycardia syndrome (Fig. 4-6). Premature complexes may be followed by long pauses before sinus node activity resumes, indicating a prolonged sinus node recovery time. Intermittent periods of accelerated junctional rhythms and variable junctional or ventricular escape rhythms may also occur.

FIG 4-6 Continuous electrocardiogram from an 11-year-old female Miniature Schnauzer with sick sinus syndrome, illustrating a combination of bradycardia and tachycardia. The top portion shows persistent sinus arrest with three different escape complexes, followed by an atrial premature complex. There is a 1-mV calibration mark in the middle of the top strip. The bradycardia is interrupted by a run of atrial tachycardia at a rate of 250 beats/min, with 1 : 1 atrioventricular conduction initially; but starting in the middle of the bottom strip, every other P’ wave is blocked (2 : 1 atrioventricular conduction).

Clinical signs can result from bradycardia and sinus arrest, paroxysmal tachycardia, or both. Signs can mimic seizures stemming from neurologic or metabolic disorders. Concurrent degenerative AV valve disease is also often present. Some dogs have evidence of CHF, usually secondary to AV valve regurgitation, although the arrhythmias may be a complicating factor.

ECG abnormalities are frequently pronounced in dogs with long-standing sick sinus syndrome. Nevertheless, some dogs have one or more normal resting ECGs. Prolonged visual ECG monitoring or 24-hour ambulatory ECG can help establish a definitive diagnosis. An atropine challenge test is done in dogs with persistent bradycardia (see p. 93). The normal response is an increase in the heart rate of 150% or to >130 to 150 beats/min. Dogs with sick sinus syndrome generally have a subnormal response.

Therapy with an anticholinergic agent, methylxanthine bronchodilator, or terbutaline given orally may temporarily help some animals that have a positive response to atropine challenge. However, anticholinergic or sympathomimetic drugs used to accelerate the sinus rate can also exacerbate tachyarrhythmias. Conversely, drugs used to suppress these supraventricular tachyarrhythmias can magnify the brady cardia, although digoxin or diltiazem is helpful in some dogs if used cautiously. Sick sinus syndrome with frequent or severe clinical signs is best managed by permanent artificial pacing. The Suggested Readings list includes sources of further details on pacing. Dogs that remain symptomatic because of paroxysmal SVTs can safely be given appropriate antiarrhythmic therapy once a normally functioning pacemaker is in place.

Atrial Standstill

Persistent atrial standstill is a rhythm disturbance characterized by lack of effective atrial electrical activity (i.e., no P waves and a flat baseline) in which a junctional or ventricular escape rhythm controls the heart. This bradyarrhythmia is rare in dogs and extremely rare in cats; most cases have occurred in English Springer Spaniels with muscular dystrophy of the fascioscapulohumeral type, although infiltrative and inflammatory diseases of the atrial myocardium can also result in atrial standstill. Because organic disease of the atrial myocardium may also involve the ventricular myocardium, persistent atrial standstill may be a harbinger of a serious and progressive cardiac disorder.

Medical treatment for persistent atrial standstill is rarely rewarding; however, an anticholinergic drug or an infusion of dopamine or isoproterenol can sometimes temporarily accelerate the escape rhythm. If ventricular tachyarrhythmias result from this treatment, the drug should be discontinued or the dose reduced. Oral terbutaline may also have some beneficial effect. Antiarrhythmic agents are contraindicated in these animals because they may suppress the escape focus, as well as the tachyarrhythmia. Permanent pacemaker implantation is the treatment of choice, although the prognosis is poor in dogs with concurrent ventricular myocardial dysfunction.

Hyperkalemia should be ruled out in animals without P waves. The apparent lack of atrial electrical and mechanical activity (“silent atrium”) caused by hyperkalemia will resolve with treatment. Sinus node activity (and P waves) become evident as the serum K⁺ concentration returns to normal.

Atrioventricular Conduction Block

Second-degree, or intermittent, AV block usually causes an irregular heartbeat. In contrast, the ventricular escape rhythm that occurs with a third-degree, or complete, AV block is regular, although premature contractions or shifts in the escape focus may cause some irregularities. AV conduction disturbances may result from therapy with certain drugs (e.g., α₂ agonists, opioids, digoxin), high vagal tone, or organic disease of the AV node. Diseases that have been associated with AV conduction disturbances include bacterial endocarditis (of the aortic valve), hypertrophic cardiomyopathy, infiltrative myocardial disease, and myocarditis. Idiopathic heart block may occur in middle-aged to older dogs; congenital third-degree heart block has also been seen in dogs. Symptomatic heart block is less common in cats, but evidence of any AV conduction disturbance should prompt further diagnostic evaluation. Most cases have been associated with hypertrophic cardiomyopathy. Heart block is occasionally found in old cats without detectable organic heart disease.

Type I second-degree AV block and first-degree AV block are frequently associated with high vagal tone or drug effects in dogs. These animals are often asymptomatic; exercise or injection of an anticholinergic drug (atropine or glycopyrrolate) usually abolishes the conduction disturbance. High-grade (many blocked P waves) second-degree AV block and complete heart block usually cause lethargy, exercise intolerance, weakness, syncope, and other signs of low cardiac output. These signs become severe when the heart rate is consistently <40 beats/min. CHF develops secondary to chronic bradycardia in some dogs, especially if other cardiac disease is present.

An atropine challenge test (p. 93) is used to determine the degree of vagal influence on the AV block. Long-term oral anticholinergic therapy (e.g., propantheline bromide) can be attempted in symptomatic animals that are atropine-responsive (see Fig. 4-5). Atropine or subsequent oral anticholinergic therapy is often ineffective, however, so artificial pacing is usually indicated. An emergency infusion of dopamine (see Box 3-1) or isoproterenol may increase the ventricular escape rate in animals with high-grade second- or third-degree block, although ventricular tachyarrhythmias may also be provoked. Oral isoproterenol is usually ineffective. A thorough cardiac workup is indicated before permanent artificial pacemaker implantation because some underlying diseases (e.g., myocardial disease, endocarditis) are associated with a poor prognosis, even after pacing. Temporary transvenous pacing is sometimes used for 1 to 2 days to assess the animal’s response to a normal heart rate before permanent pacemaker surgery is performed.

Lidocaine

Lidocaine HCl is usually the first-choice IV ventricular antiarrhythmic agent in dogs. It is often ineffective against supraventricular arrhythmias. It has little effect on sinus node rate, AV conduction rate, and refractoriness. Lidocaine suppresses automaticity in normal Purkinje fibers and diseased myocardial tissue, slows conduction, and reduces the supernormal period (during which the cell can be reexcited before complete repolarization occurs). It has greater effects on diseased and hypoxic cardiac cells and at faster stimulation rates. The electrophysiologic effects of lidocaine are dependent on the extracellular potassium concentration. Hypokalemia may render the drug ineffective, but hyperkalemia intensifies its depressant effects on cardiac membranes. Lidocaine produces little or no depression of contractility at therapeutic doses when administered slowly IV; this is useful in dogs with heart failure. The lidocaine congeners tocainide and mexiletine similarly produce minimal negative inotropic and hypotensive effects. Toxic concentrations of lidocaine can cause hypotension.

Lidocaine undergoes rapid hepatic metabolism; some metabolites may contribute to its antiarrhythmic and toxic effects. Lidocaine is not effective orally because of its almost complete first-pass hepatic elimination. IV administration, usually as slow boluses followed by CRI, is most effective. Antiarrhythmic effects after IV bolus occur within 2 minutes and abate within 10 to 20 minutes. CRI without a loading dose produces steady-state concentrations in 4 to 6 hours. The half-life is <1 hour in the dog. An initial bolus of 2 mg/kg is used in dogs and can be repeated two to three times if necessary. Lower doses should be used in cats to avoid toxicity (loading dose of 0.25 to 0.5 mg/kg). The half-life in cats is 1 to 2 hours. Therapeutic plasma concentrations are thought to range from 1.5 to 6 μg/ml in dogs. Only lidocaine without epinephrine should be used for antiarrhythmic therapy. If IV access is not possible, IM administration could be used, but IV is much preferred.

The most common toxic effect of lidocaine is central nervous system excitation. Signs include agitation, disorientation, muscle twitches, nystagmus, and generalized seizures. The latter may require diazepam (0.25 to 0.5 mg/kg IV) or a short-acting barbiturate. Nausea can also occur. Worsening of arrhythmias (a proarrhythmic effect) is seen occasionally, as it is with any drug having cardiac electrophysiologic effects. Cats are particularly sensitive to the drug’s toxic effects and may undergo respiratory arrest along with seizures. In the event of toxicity, lidocaine should be discontinued until the signs of toxicity disappear; a lower infusion rate may then be instituted. IV diazepam (0.25 to 0.5 mg/kg) is used to control lidocaine-induced seizures. There are anecdotal reports of respiratory depression and arrest after the administration of lidocaine in unconscious dogs and cats. Propranolol, cimetidine, and other drugs that decrease liver blood flow slow the metabolism of lidocaine and predispose to the development of toxicity. Animals with heart failure may also have reduced hepatic blood flow and may require a lower dosage of the drug. Hepatic disease can delay elimination as well.

Procainamide

Procainamide HCl has electrophysiologic effects similar to those of quinidine. Procainamide has both direct and indirect (vagolytic) effects; it is indicated for the treatment of premature ventricular (and sometimes atrial) depolarizations and tachycardias. It is less effective than quinidine in managing atrial arrhythmias and is usually not effective in converting chronic atrial flutter-fibrillation to sinus rhythm. Procainamide should be used only with caution in animals with hypotension.

Orally administered procainamide is well absorbed in the dog but has a half-life of only 2.5 to 4 hours. The sustained-release preparation has a slightly longer half-life of 3 to 6 hours. Food may delay the absorption of procainamide. The drug undergoes hepatic metabolism and renal excretion in proportion to the creatinine clearance. The metabolite N-acetylprocainamide is not clinically important in dogs and cats. Procainamide can be given orally or intramuscularly without marked hemodynamic effects, but rapid IV injection can cause hypotension and cardiac depression, although to a much lesser degree than IV quinidine. Administration by CRI can be useful if the arrhythmia responds to an IV bolus; a steady state is reached in 12 to 22 hours. Therapeutic plasma concentrations are thought to be 4 to 10 μg/ml.

The toxic effects of procainamide are similar to those of quinidine (discussed in the following section) but are usually milder. Gastrointestinal upset and prolongation of the QRS or QT intervals may occur. Procainamide can enhance the ventricular response rate to AF if used without digoxin or a β- or Ca⁺⁺ blocker. More serious toxic effects include hypotension, depressed AV conduction (sometimes causing second- or third-degree heart block), and proarrhythmia. The latter can cause syncope or VF. Hypotension responds to IV fluids, catecholamines, or calcium-containing solutions. Gastrointestinal signs associated with oral therapy may respond to dosage reduction. High-dose oral procainamide therapy in people has been associated with a reversible lupuslike syndrome characterized by neutropenia, fever, depression, and hepatomegaly, but this has not been documented in dogs. Long-term use can cause brown discoloration of the haircoat in black Doberman Pinschers.

Quinidine

Quinidine has been used to treat ventricular and, occasionally, supraventricular tachyarrhythmias. In large dogs with recent-onset AF and normal ventricular function, quinidine may cause conversion to sinus rhythm. This drug must be used cautiously in animals with heart failure or hyperkalemia. The characteristic electrophysiologic effects of quinidine are depression of automaticity and conduction velocity and prolongation of the effective refractory period. Corresponding dose-dependent ECG changes (e.g., PR, QRS, and QT prolongation) result from direct electrophysiologic and vagolytic effects. At low doses, quinidine’s vagolytic effects may increase the sinus rate or the ventricular response rate to AF by antagonizing the drug’s direct effects. As with other class I agents, hypokalemia reduces quinidine’s antiarrhythmic effectiveness.

The drug is well-absorbed orally but has fallen out of favor for chronic oral therapy because of its frequent adverse effects and its interference with digoxin pharmacokinetics. Quinidine is metabolized extensively by the liver, with little dependence on liver blood flow. The half-life is about 6 hours in dogs and 2 hours in cats. Quinidine is highly protein-bound; severe hypoalbuminemia can predispose to toxicity. Cimetidine can also predispose to toxicity by slowing the drug’s elimination. Quinidine can precipitate digoxin toxicity (when used concurrently) by displacing digoxin from skeletal muscle binding sites and reducing its renal clearance. Anticonvulsants and other drugs that induce hepatic microsomal enzymes can speed quinidine’s metabolism. IV administration is not recommended because of quinidine’s propensity to cause vasodilation (by means of nonspecific α-adrenergic receptor blockade), cardiac depression, and hypotension. The oral and IM routes usually do not cause adverse hemodynamic effects, but close monitoring is warranted initially, especially in animals with underlying cardiac disease. Therapeutic blood concentrations are thought to be 2.5 to 5 μg/ml and are usually achieved in 12 to 24 hours after oral and IM administration. Slow-release sulfate (83% active drug), gluconate (62% active drug), and polygalacturonate (80% active drug) salts of quinidine prolong the drug’s absorption and elimination. The sulfate salt is more rapidly absorbed than the gluconate; peak effect is usually achieved 1 to 2 hours after oral administration.

Quinidine toxicity occurs as an extension of the drug’s electrophysiologic and hemodynamic actions. As the plasma concentration increases, the PR interval and QRS duration lengthen. Marked QT prolongation, right bundle-branch block, or QRS widening >25% of pretreatment value suggests drug toxicity; various conduction blocks and ventricular tachyarrhythmias are other manifestations. Marked QT prolongation implies increased temporal dispersion of myocardial refractoriness; this predisposes to torsades de pointes (see p. 25) and VF. Transient episodes of these serious arrhythmias can be a cause of syncopal attacks in people taking quinidine. Lethargy, weakness, and CHF can result from the negative inotropic and vasodilatory effects of the drug and subsequent hypotension. Cardiotoxicity and hypotension can be partially reversed by sodium bicarbonate (1 mEq/kg IV), which temporarily decreases serum K⁺ concentration, enhances quinidine’s binding to albumin, and reduces its cardiac electrophysiologic effects. Gastrointestinal signs (e.g., nausea, vomiting, diarrhea) are common with orally administered quinidine. Thrombocytopenia (reversible after quinidine discontinuation) can occur in people and possibly in dogs and cats.

Mexiletine

Mexiletine HCl is similar to lidocaine in its electrophysiologic, hemodynamic, toxic, and antiarrhythmic properties. It can be effective in suppressing ventricular tachyarrhythmias in dogs. The combination of a β-blocker (or procainamide or quinidine) with mexiletine may be more efficacious and associated with fewer adverse effects than mexiletine alone. The drug is easily absorbed when administered orally, but antacids, cimetidine, and narcotics reportedly slow its absorption in people. Mexiletine undergoes hepatic metabolism (influenced by liver blood flow) and some renal excretion (which is slower if the urine is alkaline). Hepatic microsomal enzyme inducers may accelerate its clearance. The half-life in dogs is from 4.5 to 7 hours (depending to some degree on the urine pH). Approximately 70% of the drug is protein bound. The therapeutic serum concentration is thought to range from 0.5 to 2.0 μg/ml (as in people). The effects of this drug in cats are not known. Adverse effects have included vomiting, anorexia, tremor, disorientation, sinus bradycardia, and thrombocytopenia. Overall, mexiletine appears to produce fewer adverse effects than tocainide.

Phenytoin

Phenytoin’s electrophysiologic effects are similar to those of lidocaine. It also has some slow-calcium channel inhibitory and central nervous system effects that may contribute to its effectiveness against digitalis-induced arrhythmias. This drug is currently used only for digitalis-induced ventricular arrhythmias that have not responded to lidocaine in dogs. Its contraindications are the same as for lidocaine. Slow IV infusion and oral administration do not cause relevant hemodynamic disturbances; however, the oral bioavailability of phenytoin is poor. Rapid IV injection should be avoided because the propylene glycol vehicle can depress myocardial contractility, exacerbate arrhythmias, and cause vasodilation, hypotension, or respiratory arrest. The half-life of phenytoin in the dog is about 3 hours. The drug is metabolized in the liver, and it may speed up its own elimination by stimulating hepatic microsomal enzymes. Co-administration of cimetidine, chloramphenicol, and other drugs that inhibit microsomal enzyme activity increases phenytoin’s serum concentration. The IV administration of phenytoin has been associated with bradycardia, AV blocks, ventricular tachycardia, and cardiac arrest. Other manifestations of phenytoin toxicity include central nervous system signs (e.g., depression, nystagmus, disorientation, ataxia). The drug is not used in cats because its half-life is >40 hours, and even low doses produce toxic serum concentrations in this species.

Other Class I Agents

Disopyramide is similar to quinidine and procainamide electrophysiologically. It has a very short half-life in the dog (<2 hours), as well as marked depressive effects on the canine myocardium. Tocainide, a class IB agent similar to lidocaine, is no longer available in the United States. Flecainide and propafenone are class IC agents. They produce marked reduction in cardiac conduction velocity but have little effect on sinus rate or refractoriness. High doses depress automaticity in the sinus node and specialized conducting tissues. Vasodilation and myocardial depression can result in severe hypotension after IV injection, especially in animals with underlying cardiac disease. Proarrhythmia is a serious potential adverse effect of these agents. Bradycardia, intraventricular conduction disturbance, and consistent (although transient) hypotension, as well as nausea, vomiting, and anorexia, have occurred in dogs. Flecainide (and encainide) have been associated with increased mortality in people. These agents are rarely (and cautiously) used for treating life-threatening ventricular arrhythmias refractory to other therapy.

Propranolol

Propranolol HCl is a nonselective β-blocker that was widely used in dogs and cats, although atenolol is used more often now. Propranolol is not recommended for patients with pulmonary edema because of the potential for bronchoconstriction caused by β₂-receptor antagonism. The β₂-receptor blocking effects of propranolol also make it relatively contraindicated in patients with asthma or chronic small airway disease.

Propranolol undergoes extensive first-pass hepatic metabolism, so oral bioavailability is low; but with time and use of higher doses hepatic enzymes become saturated and bioavailability increases. Propranolol reduces hepatic blood flow, which prolongs its elimination as well as that of other drugs dependent on liver blood flow for their metabolism (e.g., lidocaine). Feeding delays oral absorption and increases drug clearance after IV dosing (by increasing hepatic blood flow). The half-life of propranolol in the dog is only about 1.5 hours (0.5 to 4.2 hours in cats). Active metabolites exist and dosing every 8 hours appears to be adequate in both species. IV propranolol is used mainly for refractory ventricular tachycardia (in conjunction with a class I drug) and for emergency treatment of atrial or junctional tachycardia.

Toxicity is most often related to excessive β-blockade; this can develop at relatively low doses in some animals. Bradycardia, heart failure, hypotension, bronchospasm, and hypoglycemia can occur. Infusion of a catecholamine (e.g., dopamine or dobutamine) will help reverse these effects. Propranolol and other lipophilic β-blockers can cause central nervous system effects such as depressed attitude and disorientation.

Atenolol

Atenolol is a selective β₁-blocker. It is used commonly to slow sinus rate and AV conduction and to suppress ventricular premature beats. The half-life of atenolol is slightly more than 3 hours in dogs and about 3.5 hours in cats. Its oral bioavailability in both species is high (∼90%). Atenolol is excreted in the urine, so renal dysfunction delays its clearance. Atenolol’s β-blocking effect lasts more than 12 hours but less than 24 hours in normal cats. This drug is hydrophilic. Adverse central nervous system effects are unlikely because it does not readily cross the blood-brain barrier. As with other β-blockers, weakness or exacerbation of heart failure can occur.

Metoprolol

Metoprolol tartrate is another β₁-selective agent. It is well absorbed orally, but bioavailability is reduced by a large first-pass effect. There is minimal protein-binding. The drug is metabolized in the liver and excreted in the urine. Half-life is 1.6 hours in dogs and 1.3 hours in cats. Metoprolol has been used in some dogs with dilated cardiomyopathy and chronic valvular disease. It may possibly contribute to improved cardiac function over time (see p. 69).

Esmolol

Esmolol HCl is an ultra-short acting β₁-selective agent. It is rapidly metabolized by blood esterases and has a half-life of <10 minutes. Steady state occurs in 5 minutes after a loading dose or 30 minutes without. Esmolol’s effects are gone within 10 to 20 minutes after infusion is terminated. This drug is used for acute therapy of tachyarrhythmias and feline hypertrophic obstructive cardiomyopathy.

Other β-Blockers

Many other β-blocking drugs are available. Their receptor selectivity as well as their pharmacologic characteristic vary. Certain β-blockers may prove useful in patients with chronic, stable myocardial failure by reducing the cardiotoxic effects of excessive sympathetic stimulation, improving cardiac function, promoting upregulation of cardiac β-receptors, and increasing survival time (see p. 69). The third-generation β-blocker, carvedilol, and the second-generation agent, metoprolol, are effective in this regard. Nonselective (first-generation) agents, such as propranolol, and some later-generation agents do not appear to confer these survival benefits. Agents with intrinsic sympathomimetic activity appear to have deleterious effects.

Sotalol

Sotalol HCl is a nonselective β-blocker that has Class III effects at higher doses. Its oral bioavailability is high, although absorption is reduced when given with food. Sotalol’s half-life is about 5 hours in dogs. It is eliminated unchanged by the kidneys, and renal dysfunction prolongs elimination. Sotalol’s β-blocking effect outlasts its plasma half-life. The drug has minimal hemodynamic effects, although it can cause slowed sinus rate, first-degree AV block, and hypotension. Proarrhythmia can occur (as with all antiarrhythmic agents), including torsades de pointes. Sotalol’s class III effects occur at higher doses in dogs than in people. Doses used clinically in dogs may be producing primarily β-blocking effects. On the other hand, a high incidence of proarrhythmia (especially torsades de pointes), of concern in people taking sotalol, has not been reported clinically in dogs. Experimentally, in dogs with hypokalemia, co-administration of mexiletine reduced the proarrhythmic potential.

Sotalol may worsen heart failure in animals with dilated cardiomyopathy. However, sotalol is thought to have less negative inotropic effect than propranolol. Other adverse effects of sotalol have included hypotension, depression, nausea, vomiting, diarrhea, and bradycardia. There are occasional anecdotal reports of aggression that resolved after sotalol was discontinued.

Amiodarone

Amiodarone HCl is thought to produce its antiarrhythmic effects by prolonging the action potential duration and effective refractory period in both atrial and ventricular tissues. Although considered a class III agent, it shares properties with all three other antiarrhythmic drug classes. Amio-darone is an iodinated compound that also has noncompetitive α₁- and β-blocking effects, as well as Ca⁺⁺ channel-blocking effects. The β-blocking effects occur soon after administration, but maximal class III effects (and prolongation of action potential duration and QT interval) are not achieved for weeks with chronic administration. Its Ca⁺⁺ blocking effects may inhibit triggered arrhythmias by reducing afterdepolarizations. Therapeutic doses slow the sinus rate, decrease AV conduction velocity, and minimally depress myocardial contractility and blood pressure. Indications for amiodarone include refractory atrial and ventricular tachyarrhythmias, especially reentrant arrhythmias using an accessory pathway. The IV form is used in people with AF, ventricular tachycardia, and during cardiopulmonary resuscitation from recurrent ventricular tachycardia and fibrillation; similar applications are expected in dogs. However, conservative dosing with slow injection over 10 to 20 minutes is recommended, because IV use can cause hypotension and bradycardia. The drug is also given by CRI in people; 10 to 15 mg/kg/day has been used in children.

The pharmacokinetics of amiodarone are complex. Chronic oral use is associated with a prolonged time to steady state (of several weeks), concentration of drug in myocardial and other tissues, and accumulation of an active metabolite (desethylamiodarone). Therapeutic serum concentration is thought to be 1 to 2.5 μg/ml. Amiodarone may have less of a proarrhythmic effect than other agents and may reduce the risk of sudden death because of uniform prolongation of repolarization throughout the ventricles, as well as suppression of Purkinje fiber automaticity. In normal dogs IV amiodarone does not adversely affect contractility at cumulative doses less than 12.5 to 15 mg/kg. However, the potential exists for more profound cardiac depression and hypotension in dogs with myocardial disease. Amiodarone use is not described in cats.

Long-term amiodarone is associated with many potential adverse effects, including depressed appetite, gastrointestinal upset, pneumonitis leading to pulmonary fibrosis, hepatopathy, thyroid dysfunction, positive Coombs test, thrombocytopenia, and neutropenia. Occasional hypersensitivity reactions (with acute angioedema formation) or of tremors have occurred in dogs. Other adverse effects observed in people have included corneal microdeposits, photosensitivity, bluish skin discoloration, and peripheral neuro-pathy. Amiodarone can increase the serum concentration of digoxin, diltiazem, and possibly procainamide and quinidine.

Other Class III Agents

Ibutilide fumarate is somewhat effective for converting recent-onset AF in people, but there is little veterinary experience with this drug. In experimental rapid-pacing–induced cardiomyopathy in dogs, ibutilide caused episodes of torsades de pointes.

Dofetilide is another drug that selectively blocks the rapid component of the K⁺ current responsible for repolarization. It too is used in people for the conversion of AF and to maintain sinus rhythm. Its efficacy for this appears to be comparable to that of other class III drugs, and it does not exacerbate left ventricular dysfunction. Bretylium tosylate is no longer available in the United States.

Diltiazem

Diltiazem HCl is a benzothiazepine Ca⁺⁺ channel blocker. It slows AV conduction, causes potent coronary and mild peripheral vasodilation, and has a lesser negative inotropic effect than the prototypical calcium entry blocker, verapamil. Diltiazem is often combined with digoxin to further slow the ventricular response rate to AF in dogs. It is indicated for other supraventricular tachyarrhythmias as well. Diltiazem is often used in cats with hypertrophic cardiomyopathy; its beneficial effects can include enhanced myocardial relaxation and perfusion, as well as a mild decrease in heart rate, contractility, and myocardial oxygen demand (see Chapter 8). Chronic diltiazem therapy may be associated with a decrease in left ventricular wall and septal thickness in cats with hypertrophic cardiomyopathy.

Peak effects are seen within 2 hours of oral dosing, and the effects last at least 6 hours in dogs. Extensive first-pass effect limits bioavailability, especially in dogs. The half-life of diltiazem in the dog is just over 2 hours, but chronic oral treatment prolongs it because of enterohepatic circulation. In cats plasma diltiazem concentration peaks in 30 minutes, and the effects last for 8 hours. The therapeutic range is 50 to 300 ng/ml. Diltiazem is metabolized in the liver; active metabolites exist. Drugs that inhibit hepatic enzyme systems (e.g., cimetidine) decrease the metabolism of diltiazem. Propranolol and diltiazem reduce each other’s clearance when used simultaneously. A sustained-release preparation (Cardizem-CD), at 10 mg/kg daily in cats, produces plasma concentrations that peak in 6 hours and remain in the therapeutic range for 24 hours. A dose of 45 mg per cat is approximately equal to 105 mg of Cardizem-CD (or the amount that fits into the small end of a No. 4 gelatin capsule; a 300-mg capsule provides about 6.5 doses); this is given once daily. Diltiazem XR is another sustained-release diltiazem preparation. The 240-mg capsule contains four 60-mg tablets. There is much intercat variability in pharmacokinetics with this form. Higher doses are more likely to be associated with anorexia and other gastrointestinal signs.

Adverse effects of diltiazem are uncommon at therapeutic doses, although anorexia, nausea, and bradycardia may occur. Rarely, other gastrointestinal, cardiac, and neurologic adverse effects develop. High liver enzyme activities and anorexia occur sporadically in cats. Some cats have become aggressive or shown other personality change when treated with diltiazem.

Verapamil

Verapamil HCl is a phenylalkylamine and has the most potent cardiac effects of the Ca⁺⁺-blockers used clinically. The drug increases the refractory period of nodal tissues and can abolish reentrant SVT as well as slow the ventricular response rate in AF. Verapamil causes dose-related slowing of the sinus rate and AV conduction. It is sometimes used for supraventricular and atrial tachycardias in animals without heart failure. Verapamil’s half-life in dogs is about 2.5 hours. It is poorly absorbed and undergoes first-pass hepatic metabolism, resulting in low bioavailability with oral use. The pharmacokinetics in cats are similar to those of dogs.

The drug has important negative inotropic and some vasodilatory effects that can cause cardiac decompensation, hypotension, and even death in the presence of underlying myocardial disease. An initially low IV dose is given very slowly; this can be repeated at 5- (or more) minute intervals if no adverse effects have occurred and the arrhythmia persists. Blood pressure monitoring is advisable because of the potential for hypotension. As discussed above, verapamil is not recommended for use in animals with heart failure. The toxic effects of verapamil include sinus bradycardia, AV block, hypotension, reduced myocardial contractility, and cardiogenic shock. Verapamil reduces the renal clearance of digoxin.

Other Calcium Channel Blockers

A number of other Ca⁺⁺-blockers are available. Most (dihydropyridine group) are used as antihypertensives. Amlodipine besylate is recommended as the first-line antihypertensive agent in cats and is also used in some hypertensive dogs (see Chapter 11). Amlodipine is also used in the treatment of chronic refractory heart failure in some dogs (see Table 3-3). The drug is not useful as an antiarrhythmic agent. Nifedipine is another potent vasodilator without antiarrhythmic effects.

Atropine and Glycopyrrolate

Anticholinergic drugs increase sinus node rate and AV conduction when vagal tone is increased (see Table 4-2). Parenteral atropine or glycopyrrolate is indicated for bradycardia or AV block induced by anesthesia, central nervous system lesions, and certain other diseases or toxicities. Atropine is a competitive muscarinic receptor antagonist that is used to determine whether excess vagal tone is responsible for arrhythmias attributed to sinus and/or AV nodal dysfunction. This is known as the atropine challenge test (or atropine response test). Response to atropine challenge is most consistent with IV administration of 0.04 mg/kg. An ECG is recorded within 5 to 10 minutes after atropine injection. If the heart rate has not increased by at least 150%, the ECG is repeated 15 (to 20) minutes after atropine injection; sometimes, an initial vagomimetic effect on the AV node lasts longer than 5 minutes. The normal sinus node response is a rate increase to 150 to 160 beats/minute (or >135 beats/minute). A positive response may not predict response to oral anticholinergic therapy. Atropine has little to no effect on bradyarrhythmias caused by intrinsic disease of the sinus or AV node.

Atropine given by any parenteral route can transiently exacerbate vagally mediated AV block when the atrial rate increases faster than AV conduction can respond. However, IV administration causes the fastest and most consistent onset and resolution of the exacerbated block, as well as the most rapid postbradycardia heart rates, compared with the IM and subcutaneous routes. Unlike atropine, glycopyrrolate does not have centrally mediated effects, and its effects are longer-lasting than those of atropine.

Oral Anticholinergic Drugs

Some animals that respond to parenteral atropine or glycopyrrolate will also respond to an oral anticholinergic agent. Clinical signs may be relieved in these animals, at least for a time. Nevertheless, animals with symptomatic bradyarrhythmias usually require permanent pacemaker implantation to effectively control heart rate. Propantheline bromide and hyoscyamine sulfate are commonly used, but other oral anticholinergic agents are also available. Individual dosage is adjusted to effect. Oral absorption of propantheline is variable; food may decrease drug absorption.

Vagolytic drugs can aggravate paroxysmal supraventricular tachyarrhythmias (as in sick sinus syndrome) and should be used only cautiously as chronic therapy in those patients. Other adverse effects of anticholinergic therapy include vomiting, dry mouth, constipation, keratoconjunctivitis sicca, increased intraocular pressure, and drying of respiratory secretions.