Toxicity in Doberman Pinchers with Ventricular Arrhythmias Treated with Amiodarone (1996–2005)

Background: Asymptomatic Doberman Pinschers with dilated cardiomyopathy (DCM) often die suddenly owing to ventricular tachycardia that degenerates into ventricular fibrillation. A safe and effective antiarrhythmic drug treatment is needed. This will require a large, well-controlled, prospective study.
Hypothesis: Amiodarone toxicity is common in Dobermans with occult DCM and ventricular tachyarrhythmias refractory to antiarrhythmia therapy. Infrequent monitoring of hepatic function is inadequate. Frequent monitoring may be useful to determine dogs in which the dosage should be decreased or the drug withdrawn.
Methods: Medical records from the University of Georgia and Cornell University were searched for Doberman Pinschers diagnosed with preclinical DCM that received amiodarone for severe ventricular arrhythmias refractory to other antiarrhythmic agents. Echocardiographic data, Holter recording data, hepatic enzyme serum activity, and serum amiodarone concentrations were recorded. The presence of clinical signs of toxicity was recorded. Serum amiodarone concentrations were obtained in some dogs.
Results: Reversible toxicity was identified in 10 of 22 (45%) dogs.
Conclusion and Clinical Importance: Adverse effects from amiodarone were common and were, in part, dosage related. Patients should be monitored for signs of toxicity and liver enzyme activity should be measured at least monthly.     

Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010)

Objectives : To evaluate the efficacy of amiodarone in dogs with refractory supraventricular and ventricular arrhythmias and to document the side effects in treated dogs. Methods : Records of 28 dogs were retrospectively searched to document indication for amiodarone administration, heart rate, alkaline phosphatase, alanine aminotransferase, thyroxine (T4) and thyroid stimulating hormone values before and after starting treatment and during follow‐up periods. Results : Sixteen dogs with supraventricular and 12 dogs with ventricular arrhythmias were treated with amiodarone. Amiodarone treatment significantly reduced the heart rate (P<0.001) and resulted in improvement in the severity of the arrhythmia and clinical signs in 26 dogs. There were no significant differences in alkaline phosphatase (P=0.596), alanine aminotransferase (P=0.842), T4 (P=0.789) and thyroid stimulating hormone (P=0.064) before and after starting amiodarone. On maintenance therapy, median amiodarone blood levels were within the accepted reference range (0.5 to 2.0 mg/L) at 0.8 mg/L (range 0.2 to 11.6 mg/L), but the majority of the desethylamiodarone levels were below normal at 0.1 mg/L (range 0.1 to 0.9 mg/L), based on human reference intervals (0.5 to 2.0 mg/L). Clinical Significance : Amiodarone may be an effective and safe alternative to treat supraventricular and ventricular arrhythmias in dogs, when common anti‐arrhythmic drugs are not effective or contraindicated.     

Effects of amiodarone on myocardial performance in normal canine hearts and canine hearts with infarcts

The effects of IV administered amiodarone, a class-III antiarrhythmic agent, on myocardial contractility, early myocardial relaxation, and hemodynamic variables were evaluated in normal canine hearts and those with infarcts. In the normal canine heart, amiodarone had important, but relatively mild, depressant effects on left ventricular contractility (assessed by maximal positive first derivative of left ventricular pressure (+dP/dtmax) and maximal elastance (Emax)) and heart rate when given IV at a dose of 10 mg/kg of body weight. An effect on contractility or active relaxation (assessed by maximal negative first derivative of left ventricular pressure (-dP/dtmax) and the time constant of isovolumic pressure decrease) was not identified with smaller doses. Myocardial infarction itself caused a predictable and marked depressant effect on myocardial contractility, as indicated by decreases in +dP/dtmax, ejection fraction, Emax, and -dP/dtmax, and elevation in end diastolic pressure. Additional depressive effects on contractility and active relaxation resulted when 10 mg of amiodarone/kg was administered to dogs with myocardial infarction and these effects were sufficient to worsen acute myocardial infarction-induced heart failure. Significant changes attributable to heart rate alone could not be identified. On the basis of our findings, we suggest that amiodarone administered IV should be used with caution in dogs with compromised ventricular function.     

Positive Coombs' test results in two dogs treated with amiodarone

Effects of amiodarone, an antiarrhythmic drug that is effective in suppressing severe ventricular arrhythmias that are refractory to other antiarrhythmic drugs, were evaluated in 2 dogs with cardiac disease. One dog was a Doberman Pinscher with cardiomyopathy that developed severe thrombocytopenia after receiving amiodarone for 7 months. The second was a Giant Schnauzer with acquired mitral valve degeneration that developed regenerative anemia after receiving amiodarone for 5 months. Results of direct Coombs' tests were positive in both dogs. Adverse effects of amiodarone are numerous; in dogs, the most common adverse effects are anorexia and hepatotoxicosis. Frequent CBC and serum biochemical analyses should be performed when amiodarone is administered with the intent of continuing the drug indefinitely.     

Hepatopathy in 4 dogs treated with amiodarone

Amiodarone is a class III antiarrhythmic drug used in dogs with dilated cardiomyopathy and ventricular tachyarrhythmias. Hepatopathy is one of the more commonly reported adverse effects of amiodarone use in people. We describe 4 dogs that developed hepatopathy associated with amiodarone administration; 2 dogs also developed neutropenia. Three dogs had clinical signs of anorexia and lethargy; 1 did not show signs until impaired liver function had developed. Clinical signs or biochemical abnormalities developed 1.5-8 months after amiodarone treatment was started. Clinical signs resolved within 2 weeks of discontinuing amiodarone, but biochemical abnormalities did not resolve for 6-8 weeks. The delay between onset of liver disease and overt clinical signs suggests that serial evaluation of liver enzyme activities following amiodarone use in does is important.     

Acute effects of escalating doses of amiodarone in isolated guinea pig hearts

Cardiac effects of escalating concentrations of amiodarone were determined on isolated perfused guinea pig hearts (Langendorff preparations). Spontaneously beating hearts were instrumented for the measurement of RR, PQ, QRS, QT and QTc durations (from a bipolar electrogram), and dP/dtmax and dP/dtmin from an isovolumetric left ventricular pressure curve. Ten hearts were exposed to escalating concentrations of amiodarone (10-7, 10-6, 10-5 and 10-4 M) in dimethyl sulfoxide (DMSO)/Krebs-Henseleit or to DMSO/Krebs-Henseleit (vehicle). Measurements were collected during the last minute of a 15-min concentration. Means of all parameters were compared by ANOVA with repeated measures design. When compared with vehicle, amiodarone prolonged QT and QTc durations at concentrations >10-6 M. The apparent lengthening of RR, PQ and QRS at concentrations >10-6 M did not achieve statistical significance. Similarly, the apparent decreases in dP/dtmax and dP/dtmin at concentrations >10-6 M did not achieve statistical significance. The putative therapeutic concentration of amiodarone is between 2 and 4 x 10-6 M. In this study, at a concentration of 10-6 M, only RR and dP/dtmin tended to change, but they were not different from vehicle. Thus, amiodarone in this preparation has little potential for cardiac toxicity at therapeutic concentrations.     

Amiodarone-induced keratopathy in healthy dogs

Amiodarone has a broad spectrum as an antiarrhythmic agent and is indicated for patients with atrial and ventricular arrhythmias. Amiodarone-induced corneal deposits are the most common reversible side effect (70-100%) in humans. Additional ocular effects in humans include deposits in the lens, retina and optic nerve. This study was conducted to determine ocular effects of chronic oral amiodarone in healthy dogs. Six chronically amiodarone-treated dogs and four controls were used for this study. Ophthalmic examination was performed using biomicroscopy and indirect ophthalmoscopy at the end of 4th, 7th and 11th weeks when dogs received amiodarone. Corneal microdeposits were observed at the end of the 7th week in one eye and at end of the 11th week in the other eye of one dog. Immediately following euthanasia, corneas and optic nerves were harvested for light and electron microscopic analysis. Light microscopic analysis showed corneal deposits in the basal epithelial cells of the cornea of the clinically affected dog. In addition, a significant increase in basal cell turnover as indicated by mitotic index was observed in the affected dog compared to both nondeposit amiodarone and control groups. All remaining animals were normal. One out of six dogs treated with amiodarone demonstrated corneal deposits (16%). This prevalence is low compared to humans. Explanations for this may include species variations particularly in volume of lacrimal secretion, or the need for longer administration. In addition, sunlight is believed to exacerbate the corneal deposits in humans and all dogs in this study were housed indoors.     

Evaluation of the pharmacokinetics and bioavailability of intravenously and orally administered amiodarone in horses

OBJECTIVE: To determine the clinical effects and pharmacokinetics of amiodarone after single doses of 5 mg/kg administered orally or intravenously. ANIMALS: 6 healthy adult horses. PROCEDURE: In a cross over study, clinical signs and electrocardiographic variables were monitored and plasma and urine samples were collected. A liquid chromatography-mass spectrometry method was used to determine the percentage of protein binding and to measure plasma and urine concentrations of amiodarone and the active metabolite desethylamiodarone. RESULTS: No adverse clinical signs were observed. After IV administration, median terminal elimination half-lives of amiodarone and desethylamiodarone were 51.1 and 75.3 hours, respectively. Clearance was 0.35 L/kg x h, and the apparent volume of distribution for amiodarone was 31.1 L/kg. The peak plasma desethylamiodarone concentration of 0.08 microg/mL was attained 2.7 hours after IV administration. Neither parent drug nor metabolite was detected in urine, and protein binding of amiodarone was 96%. After oral administration of amiodarone, absorption of amiodarone was slow and variable; bioavailability ranged from 6.0% to 33.7%. The peak plasma amiodarone concentration of 0.14 microg/mL was attained 7.0 hours after oral administration and the peak plasma desethylamiodarone concentration of 0.03 microg/mL was attained 8.0 hours after administration. Median elimination half-lives of amiodarone and desethylamiodarone were 24.1 and 58.6 hours, respectively. CONCLUSION AND CLINICAL RELEVANCE: Results indicate that the pharmacokinetic distribution of amiodarone is multicompartmental. This information is useful for determining treatment regimens for horses with arrythmias. Amiodarone has low bioavailability after oral administration, does not undergo renal excretion, and is highly protein-bound in horses.     

Permanent junctional reciprocating tachycardia in a dog

A 5-year-old male English Bulldog was presented with a 1-year history of paroxysmal supraventricular tachycardia (SVT) partially responsive to amiodarone. At admission the surface ECG showed sustained runs of a narrow QRS complex tachycardia, with a ventricular cycle length (R–R interval) of 260 ms, alternating with periods of sinus rhythm. Endocardial mapping identified the electrogenic mechanism of the SVT as a circus movement tachycardia with retrograde and decremental conduction along a concealed postero-septal atrioventricular pathway (AP) and anterograde conduction along the atrioventricular node. These characteristics were indicative of a permanent junctional reciprocating tachycardia (PJRT). Radiofrequency catheter ablation of the AP successfully terminated the PJRT, with no recurrence of tachycardia on Holter monitoring at 12 months follow-up.     

Intracardiac foreign body in a dog

A dog that was referred to the University of Florida Veterinary Medical Center was discovered to have a bamboo skewer within the right atrium and right ventricle, traversing the tricuspid valve. The skewer was ingested approximately four months prior to referral and was partially removed via gastrotomy. The presenting complaint at the time of referral included coagulopathy, anemia and leukocytosis. A linear, hyperechoic structure was identified in the right heart during an echocardiogram. The foreign body was suspected to be a portion of the skewer that the patient had previously ingested. Cardiopulmonary bypass was performed and the foreign body was removed successfully. Complications following surgery included the development of tricuspid valve and ventricular wall thrombi, atrial flutter and amiodarone toxicity. Many indications have been described in the veterinary literature for cardiopulmonary bypass. However, to the best of the authors' knowledge, successful removal of an intracardiac foreign body with cardiopulmonary bypass has not been reported in a veterinary patient. This represents a new indication for cardiopulmonary bypass in veterinary medicine.     

New perspectives in cardiology: recent advances in antiarrhythmic drug therapy

During the past decade, advances in basic and applied cardiology have led to the introduction of several new antiarrhythmic drugs that have distinct clinical advantages over their older counterparts. These therapeutic advantages comprise either a more favorable pharmacokinetic disposition in the patient or new and perhaps novel mechanisms of antiarrhythmic actions. The class IV agent verapamil, for example, selectively blocks the slow inward Ca++ current in excitable tissues and this action is proving to be quite effective in controlling supraventricular tachyarrhythmias. Tocainide is a newly approved class I agent that exerts lidocaine-like effectiveness in treating serious ventricular arrhythmias. Unlike lidocaine, however, tocainide is not restricted to intensive care because it is effective after oral administration and has comparatively longer duration of antiarrhythmic action. Other recently approved or investigational agents include bretylium and amiodarone (class III), and aprindine, mexiletine, and disopyramide (class I). Along with clinical advantages, however, each drug has a characteristic pharmacologic-toxicologic profile and resulting spectrum of therapeutic application for only particular cardiac dysrhythmias. The advantages and disadvantages of each compound should be weighed equally when the new antiarrhythmic drugs are assessed as therapeutic alternatives for the older ones.     

Effects of chronic oral amiodarone on left ventricular function,ECGs, serum chemistries,and exercise tolerance in healthy dogs

Amiodarone, a class III antiarrhythmic with beta-adrenergic blocking and antimuscarinic properties, has a wide spectrum of clinical use in humans. This study was conducted to establish the effects of a 25 mg/kg q12h loading dose and a 30 mg/kg q24h maintenance dose of amiodarone, each given PO for 3.5 weeks, on systemic arterial pressure, echocardiographic (ECHO) indices of left ventricular function, ECGs, exercise tolerance, and serum biochemistries in adult, clinically normal dogs. Means were calculated and were compared by analysis of variance with repeated measures. When a significant F statistic was identified, specific means were compared by Bonferroni's post hoc test. Body weight and heart rate (HR) decreased, and PQ, QT, and corrected QT (QTc) increased significantly (P < .05) for the weeks that the dogs received the loading dose, but all parameters returned to values the same as those in the pretest for the weeks when dogs received the maintenance dose. Serum activity of hepatic enzyme activities and cholesterol concentrations increased, and serum concentrations of thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), phosphorous, and total carbon dioxide decreased. The changes in PQ, QT, and QTc are similar to those obtained previously, but the detailed ECG and ECHO observations have not been reported. A dose of 25 mg/kg q12h, but not 30 mg/kg q24h, is an appetite suppressant, and the lower dose produces neither ECG nor ECHO changes of clinical or toxicological significance in normal dogs.     

Intravenous amiodarone treatment in horses with chronic atrial fibrillation

Six horses without underlying cardiac disease were presented because of atrial fibrillation of between 5 and 12 months duration. These horses received an intravenous amiodarone treatment of 5mg/kg/h for 1 h followed by 0.83mg/kg/h for 23h and subsequently 1.9mg/kg/h for 30h. During treatment, clinical signs were monitored and a surface ECG and an intra-atrial electrogram were recorded. Infusion was discontinued when sinus rhythm or side effects occurred. Four horses successfully cardioverted, of which one showed symptoms of hind limb weakness and weight shifting. Two horses did not cardiovert and showed similar side effects. In all horses, side effects disappeared within 6h after termination of treatment. Cardiac side effects, such as pro-arrhythmia, were not seen in any of the horses. Total bilirubin slightly increased in three horses and normalised within four days. It was concluded that amiodarone has the potential to treat naturally occurring chronic atrial fibrillation in horses, although further research is needed to refine the infusion protocol.     

Effects of an adapted intravenous amiodarone treatment protocol in horses with atrial fibrillation

REASON FOR PERFORMING STUDY: Good results have been obtained with a human amiodarone (AD) i.v. protocol in horses with chronic atrial fibrillation (AF) and a pharmacokinetic study is required for a specific i.v. amiodarone treatment protocol for horses. OBJECTIVES: To study the efficacy of this pharmacokinetic based i.v. AD protocol in horses with chronic AF. METHODS: Six horses with chronic AF were treated with an adapted AD infusion protocol. The protocol consisted of 2 phases with a loading dose followed by a maintenance infusion. In the first phase, horses received an infusion of 6.52 mg AD/kg bwt/h for 1 h followed by 1.1 mg/kg bwt/h for 47 h. In the second phase, horses received a second loading dose of 3.74 mg AD/kg bwt/h for 1 h followed by 1.31 mg/kg bwt/h for 47 h. Clinical signs were monitored, a surface ECG and an intra-atrial electrogram were recorded. AD treatment was discontinued when conversion or any side effects were observed. RESULTS: Three of the 6 horses cardioverted successfully without side effects. The other 3 horses did not convert and showed adverse effects, including diarrhoea. In the latter, there were no important circulatory problems, but the diarrhoea continued for 10-14 days. The third horse had to be subjected to euthanasia because a concomitant Salmonella infection worsened the clinical signs. CONCLUSION: The applied treatment protocol based upon pharmacokinetic data achieved clinically relevant concentrations of AD and desethylamiodarone. POTENTIAL RELEVANCE: Intravenous AD has the potential to be an alternative pharmacological treatment for AF in horses, although AD may lead to adverse drug effects, particularly with cumulative dosing.     

Clinical assessment of left ventricular relaxation

Ventricular relaxation is altered in a number of cardiac disorders affecting domestic animals. Clinical determination of the ventricular relaxation rate can provide useful information regarding disease severity and response to therapy. We believe that the current gold standard for assessing left ventricular relaxation requires measurement of ventricular luminal pressure at end-expiration using a high-fidelity catheter. Ventricular pressure should be digitized at ≥200 Hz for the period of pressure fall between the minimum rate of change of ventricular pressure and 10 mm Hg above left ventricular end-diastolic pressure of the preceding beat. The rate of relaxation then should be determined from the digitized data by Marquardt nonlinear least squares parameter estimation using an exponential decay model with nonzero asymptote. The major disadvantage in using an invasive method for evaluating left ventricular relaxation is that it requires general anesthesia in animals that frequently are categorized as high-risk anesthetic patients. Noninvasive estimates of ventricular relaxation using echocardiographic parameters such as isovolumic relaxation time, peak early filling rate, and time from end-systole to peak filling rate provide a crude and nonspecific assessment of ventricular relaxation that can be obtained from conscious animals. Determinations of these echocardiographic indices are of limited usefulness in assessing changes in ventricular relaxation associated with disease progression or therapeutic intervention, unless concurrent estimates of left atrial pressure, mitral valve characteristics, and left ventricular compliance are available.     

THE USE OF GATED RADIONUCLIDE VENTRICULOGRAPHY AS A NONINVASIVE METHOD OF EVALUATING RIGHT VENTRICULAR FUNCTION IN DOGS WITH EXPERIMENTALLY INDUCED CONGESTIVE HEART FAILURE

Gated radionuclide ventriculography was evaluated as a noninvasive method of quantifying right ventricular function in dogs with experimentally induced congestive heart failure. Gated radionuclide ventriculography measurements of right ventricular function (right ventricular ejection fraction, right ventricular average emptying rate, and right ventricular average filling rate) were related to standard hemodynamic and echocardiographic measurements. Congestive heart failure was induced by rapid ventricular pacing in eight normal dogs. Hemodynamic, echocardiographic, and gated radionuclide ventriculography measurements were obtained before and after development of biventricular failure. Congestive heart failure resulted in significant changes in all hemodynamic, echocardiographic, and gated radionuclide ventriculography measurements with the exception of systemic arterial pressure. Right ventricular ejection fraction was inversely related to pulmonary artery systolic, diastolic, and mean pressure, and right ventricular average emptying rate was inversely related to the pulmonary artery systolic, diastolic, and mean pressure. Right ventricular ejection fraction was inversely related to left ventricular filling pressure, (pulmonary capillary wedge pressure). Neither the echocardiographic measurements of right ventricular size (right ventricular internal diastolic dimension) nor the right ventricular end-diastolic pressure were related to right ventricular ejection fraction and right ventricular average emptying rate. However, echocardiographic measurements of right ventricular dimension were related to right ventricular filling pressure. The gated radionuclide ventriculography indexes of right ventricular function, right ventricular ejection fraction and right ventricular average emptying rate, are affected by afterload but unaffected by preload, whereas the echocardiographic measurement of right ventricular dimension is related to preload. Gated radionuclide ventriculography provides right ventricular data which is unique from that obtained by standard echocardiographic imaging. Also, gated radionuclide ventriculography has potential value as a noninvasive means of estimating a change in pulmonary artery pressure.     

Ventricular dyssynchrony as a cause of structural disease in the heart of Dorper sheep

Ventricular dyssynchrony is a disturbance of the normal, organized electromechanical coupling of the two ventricles. This condition has many causes, such as left bundle branch block, ventricular preexcitation, right ventricular pacing and right ventricular premature ventricular complexes (PVCs). Ventricular dyssynchrony has many adverse haemodynamic effects on the left ventricle and we wanted to know whether these adverse haemodynamic effects might have any structural consequences on the left ventricles of such hearts. Six healthy Dorper wethers were subjected to numerous right ventricular PVCs to induce ventricular dyssynchrony in order to determine whether any structural consequences will occur in the left ventricles of these hearts. Myocarditis in the musculature of the left ventricles of all six these hearts was seen.     

肉鸡腹水症发病机理研究Ⅳ.肉鸡和蛋仔鸡左右心室功能的比较研究

试验选用快速生长的艾维茵肉鸡和海兰蛋仔鸡 ,各试验组用右心导管法和左心导管法测定肺动脉压(PAP)、右心室收缩压 (RVSP)、左心室收缩压 (LVSP)、左右心室内压最大变化速率 (+dp/dt)的动态变化。并且比较了相同体重健康蛋仔鸡、肉鸡的左右心室功能变化特点。结果表明 :相同日龄肉鸡肺动脉压显著高于蛋仔鸡 ;2 8、35日龄肉鸡右心收缩压显著高于蛋仔鸡 (P <0 0 5) ,2 8、35、42和 49日龄肉鸡左心室收缩压低于蛋仔鸡 ,且差异极显著 (P <0 0 1 )。肉鸡左心室内压最大变化速率 (LV +dp/dt)从 2 1日龄测定起呈现显著性低于同日龄的蛋仔鸡。相同体重的肉鸡和蛋鸡相比 ,肉鸡肺动脉压 (PAP)显著高于蛋仔鸡 ,但肉鸡右心室内压最大变化速率 (RV +dp/dt)、左心室收缩压 (LVSP)、左心室内压最大变化速率 (LV +dp/dt)显著低于蛋仔鸡。这提示肉鸡先天存在着肺动脉压较高、左心室病理性功能低下 ,这可能是肉鸡容易发生腹水症的原因之一