Abstract
Objective—To investigate effects of IV administration of propafenone for naturally occurring and experimentally induced chronic atrial fibrillation in horses.
Animals—2 horses with naturally occurring atrial fibrillation and 4 horses with pacing-induced atrial fibrillation.
Procedures—Horses received a bolus of propafenone (2 mg/kg, IV over 15 minutes). If atrial fibrillation persisted after 20 minutes, a continuous infusion of propafenone (7 μg/kg/min) was given for 120 minutes. Before, during, and after treatment, plasma propafenone concentrations, hematologic and serum biochemical values, and electolyte concentrations analyses were determined and clinical signs were monitored. Surface ECGs were recorded. If propafenone treatment failed, quinidine sulfate was administered.
Results—Bolus and continuous infusion induced minimal adverse effects. During the 15-minute bolus administration, a slight increase in heart rate was observed and horses appeared more sensitive to external stimuli. Throughout treatment, no significant changes were observed in respiratory rate, QRS or corrected QT duration, or results of hematologic analyses. Although a significant increase in F-wave interval and atrial fibrillation cycle length was observed and plasma propafenone concentrations (569 to 1,268 ng/mL) reached the human therapeutic range (64 to 1,044 ng/mL), none of the horses cardioverted to sinus rhythm. Sinus rhythm could be restored in all horses via standard oral administration of quinidine.
Conclusions and Clinical Relevance—A slow IV bolus of 2 mg of propafenone/kg followed by a continuous infusion of 7 μg/kg/min over 2 hours was not an effective treatment for chronic atrial fibrillation in horses.
Atrial fibrillation is the most important arrhythmia in horses. Treatment is recommended in horses with atrial fibrillation in the absence of underlying heart disease because the horse's performance generally returns to the previous level after restoration to sinus rhythm. In horses, atrial fibrillation may be detected as an incidental finding because clinical signs are not always obvious, especially in pleasure horses. However, a history of exercise intolerance, exercise-induced epistaxis, respiratory tract disease, weakness, or syncope may be present.1,2 In many cases, the historical findings suggest that atrial fibrillation was present for several weeks or even months before horses were evaluated for cardioversion. It has been suggested that when atrial fibrillation persists for > 3 to 6 months or when atrial dilatation is present because of mitral valve regurgitation or atrial fibrillation per se, treatment is less effective.3,4,a
Orally administered quinidine sulfate, a class I anti-arrhythmic drug, is the drug of choice for pharmacologic treatment of acute and chronic atrial fibrillation in horses. An efficacy of 85% in horses with an atrial fibrillation duration of < 2 months and without detectable cardiac disease has been reported.1,3 Nevertheless, in up to 76% of treated horses, this drug can cause serious cardiac and noncardiac adverse effects, including urticaria, nasal edema, colic, diarrhea, laminitis, polymorphic ventricular tachycardia, anaphylactic shock, syncope, or sudden death.3,5 In addition, in some countries, quinidine sulfate is no longer available.
Although IV administration of flecainide, a class I antiarrhythmic drug, was originally reported to be efficacious in acute (experimentally induced) atrial fibrillation,6 life threatening and even lethal ventricular dysrhythmias can occur in horses with acute atrial fibrillation (author's experience) and chronic atrial fibrillation.7 Intravenous administration of cibenzoline (infusion rate, 0.1 mg/kg/min), a class I antiarrhythmic drug (with additional class III and IV properties), was unsuccessful in 2 horses with atrial fibrillation and was associated with severe ventricular proarrhythmia.8
Sotalol, a class III drug, has been used in 3 horses with atrial fibrillation (0.75 to 1.25 mg/kg, IV infusion over 15 minutes) and was not associated with adverse effects. However, sinus rhythm could not be restored.8 Intravenous administration of amiodarone, a class III antiarrhythmic drug, has been described in horses with chronic atrial fibrillation but with a moderate success rate of 50% to 67% and occurrence of important adverse effects, especially with prolonged (> 36 hours) protocols.9,10
Successful electrical cardioversion has been described for horses with atrial fibrillation.1,4,11–16 However, this technique requires general anesthesia, special equipment, and expertise, which may make the process more expensive.
Further research for alternative pharmacologic treatment options might be necessary and useful. Kochiadakis et al17 reported that propafenone appeared to be safe and moderately effective for the treatment of chronic atrial fibrillation in humans.17 The purpose of the study reported here was to investigate effects of IV administration of propafenone for naturally occurring and experimentally induced chronic atrial fibrillation in horses.
Materials and Methods
Animals—Six trotter horses with a mean ± SD age, body weight, and height at the withers of 5.6 ± 2.1 years, 517 ± 65 kg, and 158 ± 7 cm, respectively, were studied. Two of the 6 horses (horses 1 and 2) had a history of exercise intolerance and naturally occurring atrial fibrillation for 6 months and 1 year, respectively. In the 4 other horses (horses 3 through 6), atrial fibrillation had been experimentally induced and maintained as described by van Loon et al4 during a 4-month period. In these horses, a transvenous screw-in electrode was implanted in the right atrium and connected with a pacemaker to deliver repeated bursts of electrical stimuli to the atrium. Initially, cessation of burst pacing resulted in relative short episodes of atrial fibrillation. As burst pacing was continued, the induced atrial fibrillation episodes increased and became self-sustained in all horses. At the time of propafenone treatment, the mean duration of spontaneous, self-sustained atrial fibrillation was 3 months. At that time, AFCL was 138 ± 15 milliseconds, compared with 138 ± 6 milliseconds in the horses with naturally occurring atrial fibrillation.
Treatment regimen—Horses received 2 mg of propafenone/kg, IV, over 15 minutes. If atrial fibrillation persisted 20 minutes after this bolus, a continuous infusion of propafenone (rate, 7 μg/kg/min) was given for 120 minutes. Infusion was discontinued when conversion was achieved, any adverse effects were observed, or the 120-minute infusion was completed.
Recorded data—Before propafenone treatment, clinical examination, a base-apex ECG, and echocardiography were performed in all horses. Echocardiography included 2-dimensional, M-mode, and color flow Doppler. The 2-dimensional and M-mode measurements from the left cardiac window included left atrial diameter during ventricular diastole and systole and, from the right cardiac window, aortic diameter in diastole, left ventricular internal diameter in diastole and systole, interventricular septum thickness in diastole and systole, and left ven-tricular fractional shortening. Measurements were performed by 1 observer before (baseline; 0 minutes) and at 2.5, 5, 7.5, 10, 12.5, 15, 35, 60, 90, 120, 150, and 180 minutes of the study protocol. Before, during, and after propafenone treatment, clinical signs were monitored and intra-atrial electrograms and surface ECGs were recorded. From the surface ECG, heart rate, F-wave interval (milliseconds), QRS duration (milliseconds), and corrected QT interval (milliseconds) were measured. The AFCL was measured with a pacemaker and a pacemaker programmerb as described by van Loon et al.18 In these horses, a transvenous screw-in electrode had previously been implanted in the right atrium and was connected to an implantable pacemaker. The pacemaker programmer allowed direct measurement of the AFCL on an intra-atrial electrogram. In the noninstrumented horses, an 8.5-F introducer sheathc was placed in the lower half of a jugular vein. In the standing and nonsedated horse, a temporary pacing-sensing catheterd was introduced through the introducer sheath and placed under echocardiographic guidance in the right atrium. Atrial endocardomyocardial contact of the temporary pacing-sensing catheter resulted in rapid atrial deflections on the intra-atrial electrogram. The mean interval between the F waves and the AFCL was measured from a 2- to 10-second window.
Blood samples for retrospective determination of propafenone concentrations were collected at baseline and at 2.5, 5, 7.5, 10, 12.5, 15, 35, 60, 90, 120, 150, 180, 480, 720, and 1,440 minutes. The plasma concentrations were analyzed by use of a validated high-performance liquid chromatography method combined with UV detection.19 A limit of quantification of 5 ng/ mL was obtained.
Blood samples for hematologic and serum biochemical analyses were collected at baseline, after the 15-minute bolus, and 24 hours after cessation of the propafenone treatment. Variables measured were WBC count; differential count; concentrations of electrolytes, total bilirubin, creatinine, total protein, and urea nitrogen; and activities of alkaline phosphatase, aspartate aminotransferase, creatine kinase, G-glutamyl transferase, and lactate dehydrogenase.
Statistical analysis—Effects of the propafenone treatment on respiratory rate, heart rate, AFCL, F-wave interval, QRS duration, and corrected QT interval were analyzed by use of single-factor ANOVA. A Dunnett test was performed to detect possible significant (P < 0.05) differences, compared with baseline values.
Results
All electrolyte concentrations and hematologic and biochemical values were within reference ranges. Cardiac evaluation performed via auscultation, echo-cardiography (2-dimensional and M-mode), and color flow Doppler revealed normal findings, except for horse 2, which had mild mitral valve regurgitation. Left atrial diameters during diastole and systole were within reference ranges.20
Every horse received the full treatment protocol. During the 15-minute bolus administration, each horse was more sensitive to external stimuli. No other cardiac or noncardiac adverse effects were evident. Sensitivity of horses to audible or tactile stimuli disappeared gradually within 30 minutes after termination of the 15-minute bolus. Cardioversion to sinus rhythm could not be achieved.
From the numeric description of the data for respiratory rate, heart rate, AFCL, F-wave interval, QRS duration, and corrected QT interval as well as from the error bar graphs, it was concluded that the condition of equality of variances was satisfied. For the respiratory rate, heart rate, QRS duration, and corrected QT interval, statistical analysis did not reveal significant differences. However, a slight increase in heart rate was observed (Figure 1). The ANOVA revealed a significant difference in the mean values over time for AFCL and F-wave interval from 7.5 and 10 minutes onward, respectively, and a significant (P < 0.001) difference from 10 and 12.5 minutes, respectively. However, although an increase in AFCL was observed in all horses, no cardioversion was achieved.
Mean ± SD values for variables measured before (baseline; 0 minutes), during (first 15 minutes), and after treatment for atrial fibrillation in 6 horses that received propafenone at 2 mg/kg (left side of x-axis) and a subsequent constant rate infusion of 7 μg/kg for 120 minutes (right side of x-axis), IV. * Significantly different from baseline value. °Data obtained from 5 horses.
Citation: American Journal of Veterinary Research 70, 2; 10.2460/ajvr.70.2.223
Plasma propafenone concentrations during and after treatment were determined (Figure 1). Two serum samples of horse 6 were destroyed during centrifugation, and no data of these time points were available at 120 and 480 minutes. Hematologic and serum biochemical values remained within reference ranges after the 15-minute bolus administration and 24 hours after cessation of the propafenone treatment.
One week after propafenone treatment, the 4 instrumented horses and 1 horse (horse 1) with naturally occurring atrial fibrillation were treated with orally administered quinidine sulfate. Each horse had successful conversion to sinus rhythm after 2 or 3 doses of quinidine sulfate. One horse had tachycardia and QRS widening. Thirty minutes before restoration to sinus rhythm, the mean ± SD F-wave interval was 376 ± 46 milliseconds and QRS duration was 108 ± 11 milliseconds.
Discussion
Propafenone, a class I antiarrhythmic drug, is used successfully to convert atrial fibrillation of recent onset in humans with a success rate of up to 83%.21,22 As with other conventional antiarrhythmic drugs, its efficacy in long-lasting atrial fibrillation is lower. For different species, a great inter-subject variability in elimination half-life of propafenone is described. The elimination half-life after a single propafenone bolus administered IV is about 150, 83, and 120 minutes for humans, dogs, and horses, respectively.23–27 On the basis of these observations, we investigated the potential of IV administration of propafenone at a dose of 2 mg/kg to treat horses with chronic atrial fibrillation. At the time of propafenone treatment, the mean duration of spontaneous self-sustained atrial fibrillation in the instrumented horses was 3 months. For the horses with experimentally induced atrial fibrillation, atrial fibrillation induction by burst pacing was only applied for a few weeks. For the remainder of time, atrial fibrillation continued spontaneously without any further intervention. As such, atrial fibrillation in these horses was thought to resemble naturally occurring chronic atrial fibrillation. In addition, AFCL in both groups was similar (138 ± 15 milliseconds vs 138 ± 6 milliseconds). In contrast to humans, in our study, none of the horses converted to sinus rhythm. The doses used in our treatment protocol were those described for humans adapted to the weight of a horse.17,e,f
In humans, therapeutic propafenone plasma concentration is variable and ranges from 20 to 60 ng/mL,28 50 to 200 ng/mL,29 and 64 to 1,044 ng/mL.24 Steurer et al28 and Karagueuzian et al30 described a decreased propafenone efficacy at a plasma concentration < 20 ng/ mL in humans and < 500 ng/mL in dogs. In humans, values > 4,180 ng/mL are described as lethal.31 However, intersubject variability in therapeutic concentration emphasizes the need to individualize therapy to the patient.24 A pharmacokinetic study27 of propafenone in horses found a rapid elimination half-life (1 to 2 hours) after a single bolus of 2 mg/kg. However, injection rate was not mentioned, and clinical signs, surface ECGs, and other values were not measured. Because of the rapid decline in plasma concentrations, these authors suggested the use of a continuous infusion for administration of the drug without mentioning a dose protocol.27
With our treatment protocol (2 mg/kg), which was a dosage higher than that suggested for the management of ventricular arrhythmia,32 horses reached the lower therapeutic concentration of 20 to 500 ng/mL.
However, this resulted in significant prolongation of AFCL, suggesting a significant slowing of conduction at the atrial level at this propafenone concentration. This effect was obtained without important adverse reactions. The administration of a higher dosage of propafenone could result in a further increase of AFCL but with a higher risk of major adverse effects. We observed with flecainide, another class Ic antiarrhythmic drug, a prolongation of the AFCL to a median of 200 milliseconds and a prolongation of the QRS complex to 130 milliseconds.7 This was associated with development of serious, potentially life-threatening ventricular arrhythmia. Furthermore, we previously observed in a horse the development of ventricular tachycardia with wide QRS complexes progressing to ventricular fibrillation and asystole with 2 mg of fle-cainide/kg. The preceding QRS duration was 140 milli-seconds, and AFCL was 286 milliseconds. On the basis of these observations, we limited the dosage of propafe-none to 2 mg/kg to avoid QRS prolongation, an early marker for development of ventricular proarrhythmia.
In contrast to propafenone, quinidine sulfate treatment resulted in the termination of atrial fibrillation in all horses in the present study. The degree of AFCL prolongation was much more pronounced after quinidine, compared with propafenone. This results in an increased reduction of the mean number of fibrillation waves, increasing the statistical chance of termination of atrial fibrillation.33
In human medicine, adverse effects caused by administration of propafenone include cardiac, hepatic, cholestatic, dermatologic, and nervous system disorders.34–39 In case of cardiac adverse reactions, some authors describe successful therapy with administration of alkalinizing solutions (eg, bicarbonate) or rifampicin to increase metabolism of propafenone.40–42 In the present study, no important adverse effect of propafenone in the given dose was observed.
In the present study, IV propafenone treatment in horses with naturally occurring or induced chronic atrial fibrillation resulted in significant electrophysiologic changes in the right atrium but did not result in atrial fibrillation termination. Overall, the value of class Ic antiarrhythmic drugs in termination of atrial fibrillation in horses seems limited.
ABBREVIATIONS
| AFCL | Atrial fibrillation cycle length |
van Loon G, Tavernier R, Fonteyne W, et al. Pacing induced longterm atrial fibrillation in horses (abstr). Europace 2001;2(suppl A):84.
Programmer 9790, Medtronic, Minneapolis, Minn.
Intro-Flex, Baxter, Freiburg, Germany.
U.S.C.I., Bard, Ireland.
Capucci A, Lenzi T, Boriani G, et al. Efficacy of propafenone to convert atrial fibrillation to sinus rhythm: a controlled study comparing acute intravenous infusion vs oral loading (abstr). Circulation 1993;88:I-445.
Lavanga S, Lolli G, Mendia R, et al. Efficacy of intravenous boli of propafenone in converting persistent paroxysmal atrial fibrillation to sinus rhythm (abstr). Circulation 1991;84:II-126.
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