Rapid control of refractory atrial tachyarrhythmias with high-dose oral amiodarone.

To shorten the delay in the onset of antiarrhythmic effect when using amiodarone for the conversion of refractory atrial tachyarrhythmias to sinus rhythm, 19 patients were given oral amiodarone according to a high-dose loading protocol. In 18 of 19 patients (95%), sinus rhythm was restored 36 hours (range, 0 to 96 hours) after starting amiodarone. The conversion occurred as a result of amiodarone therapy alone within 48 hours in 12 patients (63%), and by amiodarone therapy plus electrical cardioversion at 48 to 96 hours in six patients (32%). Minor side effects were noted in eight patients (42%). No major side effects were encountered. The length of hospital stay after initiating amiodarone therapy was 3.6 days (range, 2 to 5 days). High-dose oral amiodarone loading is a safe and effective method for the rapid conversion of atrial tachyarrhythmias to sinus rhythm.

A general overview of amiodarone toxicity: its prevention, detection, and management.

Although amiodarone is a highly effective antiarrhythmic agent, it has a high incidence of side effects, some of which can be serious or even lethal. With close monitoring, side effects can be found in essentially all patients, but fortunately most of these are mild and well tolerated. Furthermore, many will respond to dosage reduction in a relatively short period of time, ie, days to weeks, which is remarkable considering the long period of time amiodarone has been shown to persist in tissues. There is reasonable evidence that toxicity, particularly the early toxic manifestations with large loading dosages, can be favorably modified by reducing the dosage. Similarly, reducing the maintenance dosage will, in most instances, reduce or eliminate most toxic manifestations. The mechanisms of toxic effects are uncertain, but suggestive evidence exists for and against both an immunologic reaction and an intracellular lysosomal lipoidosis. Principles of use of amiodarone should include individualizing administration of dosages for each patient due to the unusual pharmacokinetic properties of this drug and continuous long-term attempts at using the lowest effective dosage. There are no definite tests that predict amiodarone efficacy or toxicity, but the serum level can be used as a rough guide of absorption and distribution in the attempt to minimize the maintenance dosage. No guidelines regarding screening tests for toxicity can be made at this time since great variability in these tests has been reported, and no evidence exists for their benefit in preventing adverse effects to amiodarone. However, follow-up testing at the intervals noted in the package insert are reasonable and important. The possibility of interactions with drugs already reported and with others not yet reported should always be kept in mind, and appropriate monitoring for clinical evidence of toxicity due to the concomitantly used drugs should be undertaken. Amiodarone can have a tremendous beneficial effect in the proper circumstances, but it is a drug that should command utmost respect because of its side effects and requires constant vigilance from any physician wishing to use it.

Relative tachycardia in ambulant children with borderline hypertension.

Borderline hypertensives who demonstrate tachycardia have a tendency toward the development of essential hypertension. However, the documentation of tachycardia in previous studies has been generally based on brief periods of observation. In the present study, we measured heart rates through a 24-hour period in 16 ambulatory mildly hypertensive subjects (ages 5 to 23 years). When compared with normal matched controls, significantly (p less than 0.05) higher heart rates were observed during the waking periods (99 +/- 9 vs 90 +/- 11) and sleep periods (72 +/- 12 vs 62 +/- 7). Similar observations were also made for 24 hours (90 +/- 8 vs 79 +/- 8). In addition, hypertensives also demonstrated thickened (during diastole) left ventricular posterior wall (0.96 +/- 0.17 vs 0.85 +/- 0.13 cm; p less than 0.05) and interventricular septum (0.98 +/- 0.17 vs 0.84 +/- 0.19 cm; p less than 0.05). It is suggested that tachycardia may be an early manifestation of borderline hypertension in children.

Rapid suppression of complex ventricular arrhythmias with high-dose oral amiodarone.

Although amiodarone is effective for the suppression of complex ventricular arrhythmias, a major problem with its use is the long delay between the initiation of therapy and the onset of effective suppression of arrhythmia. To test the hypothesis that rapid loading with oral amiodarone to a target serum concentration can overcome much of this delay, eight patients with refractory, sustained, hemodynamically compromising ventricular arrhythmias and 10 patients with potentially life-threatening ventricular arrhythmias were treated with a flexible, very high dose, oral loading protocol (800 to 2000 mg two to three times a day). Dosage was adjusted on the basis of amiodarone serum concentrations to maintain the trough serum concentrations between 2.0 and 3.0 micrograms/ml. Comparison of 24 hr Holter electrocardiograms obtained before and during therapy revealed statistically significant reductions in premature ventricular complexes (PVCs) and paired PVCs beginning the first day of therapy and a reduction in ventricular tachycardia (VT) beginning the second day. By day 2, four of eight patients with sustained VT and six of 10 patients with nonsustained VT showed no VT. Pulmonary arterial catheterization during the first 24 hr (mean amiodarone dose 3933 mg) revealed no significant hemodynamic alterations. Minor side effects were common (10 patients) but major side effects were rare (one patient). High-dose oral loading with amiodarone utilizing serum concentration guidelines is a safe and effective method of rapidly controlling life-threatening arrhythmias in selected patients.

Amiodarone: correlation of serum concentration with suppression of complex ventricular ectopic activity.

Although amiodarone has been used for the suppression of complex ventricular arrhythmias since the early 1970s, there is a paucity of information regarding the relation of serum concentration to arrhythmia suppression. To investigate this relation, 25 patients receiving chronic amiodarone therapy for complex ventricular arrhythmias were retrospectively studied. At each visit a blood sample for determination of trough serum amiodarone concentration and a 24-hour 2-channel ambulatory electrocardiogram (ECG) were obtained. Dosage was adjusted, based on the ambulatory ECG, to maintain arrhythmia suppression at the lowest possible amiodarone dose and, hence, because of the extremely long half-life of amiodarone, patients were rarely in a true steady state. Over 17 months, 218 ambulatory ECGs with corresponding serum samples were analyzed. Negative correlations between serum amiodarone concentration and the frequencies of premature ventricular complexes (PVCs), paired PVCs and ventricular tachycardia were found (p less than 0.005, p less than 0.005 and p less than 0.05, respectively). No correlations existed between amiodarone dose and these arrhythmias. Trough serum amiodarone concentrations greater than 2.0 micrograms/ml were associated with significant reductions in the frequencies of PVCs (p less than 0.01) and paired PVCs (p less than 0.02) when compared with serum concentrations below this level. A reduction in ventricular tachycardia was seen with serum concentrations greater than 1.5 micrograms/ml (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone: intravenous loading for rapid suppression of complex ventricular arrhythmias.

A major disadvantage of conventional amiodarone therapy is the long delay between initiation of therapy and arrhythmia suppression. In this study, the hypothesis was tested that complex ventricular arrhythmias would be suppressed rapidly by an intravenous amiodarone infusion designed to achieve and maintain a therapeutic serum concentration. Eleven patients were studied. Each underwent a single intravenous dose kinetic study, followed by a two stage infusion of amiodarone that achieved and maintained a serum concentration of 2 to 3 micrograms/ml. In seven patients, arrhythmias during hours 24 to 48 after the infusion were compared with arrhythmias without therapy. Amiodarone therapy reduced episodes of ventricular tachycardia by 85% (p less than 0.01), paired premature ventricular complexes by 74% (p less than 0.01) and premature ventricular complexes by 60% (p less than 0.05). Four patients could not tolerate a control period without therapy because of symptomatic arrhythmias. In three patients, symptomatic arrhythmias were abolished during the 24 hour evaluation period. Two of 11 patients, both with severe left ventricular dysfunction, developed significant hypotension during the loading phase of the infusion. It is concluded that the achievement and maintenance of a therapeutic serum concentration of intravenous amiodarone are effective in the rapid suppression of life-threatening ventricular arrhythmias. Caution should be employed when using large intravenous doses in patients with severely impaired left ventricular function.

Amiodarone-digoxin interaction. Clinical and experimental observations.

Twenty-two patients were given amiodarone for refractory cardiac arrhythmias, and pre- and post-amiodarone serum digoxin levels were studied. The interval between pre- and post-amiodarone serum digoxin levels ranged from five days to nine months (mean interval, seven weeks). The mean (+/- SD) pre-amiodarone serum digoxin level was 1.0 +/- 0.4 ng/ml, and the post-amiodarone serum digoxin level was 1.9 +/- 0.8 ng/ml (p less than .001). To develop an animal model for study of the digoxin-amiodarone interaction, 18 pigs were given digoxin for a four-week period. Half of the animals were given amiodarone as well as digoxin for the last two weeks of the study. At the end of the initial two-week period, there was no difference in serum digoxin levels between the two groups. At the end of the second two-week period, the serum digoxin level in the group receiving digoxin alone was 0.6 +/- 0.2 ng/ml, and the serum digoxin level in the group receiving the digoxin and amiodarone was 1.2 +/- 0.6 ng/ml (p less than .01). These data confirm the presence of an amiodarone-digoxin interaction in man and show that the pig is an appropriate model for study of this clinical phenomenon in the animal laboratory.

Amiodarone pulmonary toxicity.

Of the side effects that complicate amiodarone therapy, pulmonary fibrosis is potentially the most serious. Therefore, the development of techniques to predict the onset of this troublesome reaction would be of great practical value. Reports of 39 patients who developed pulmonary toxicity with amiodarone were evaluated for clues to precipitating factors and information on the response to corticosteroid treatment. The majority of patients were being given maintenance doses greater than 400 mg/day. Patients appeared to improve after withdrawal of amiodarone, both with and without corticosteroid treatment. In addition, a case report is presented of a patient who developed pulmonary changes that disappeared when amiodarone was withdrawn and did not recur when amiodarone was reinstituted. Data from sequential pulmonary function tests and cumulative amiodarone dosage in 35 patients were also examined to determine their value in predicting pulmonary complications. Pulmonary function tests did not appear to be useful in predicting the likelihood of an individual patient's developing pulmonary complications. Although none of the available information identifies the mechanism mediating amiodarone pulmonary toxicity, the frequency of the complication probably can be reduced by timely reductions in maintenance dosage.

Determination of amiodarone and its N-deethylated metabolite in serum by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method utilizing hexane extraction and a normal bonded phase column (NH2-alkylamine) was developed to measure serum concentrations of amiodarone and its N-deethylated metabolite. A single analysis requires 8 min. The one-step extraction efficiencies of amiodarone and the internal standard are greater than 90%. The method is linear between 0.05 and 20.0 micrograms/ml. The average relative standard deviation of the slope of the standard curve is 4% and the single day coefficient of variation is 3.2%. The use of hexane extraction for sample cleanup and a bonded phase column for chromatography result in a sensitive and reproducible system well suited to laboratories monitoring serum concentrations of multiple drugs by HPLC. A preliminary study has shown the assay to be useful for the investigation of the pharmacokinetics of this agent.

Amiodarone in the treatment of refractory ventricular arrhythmias. Importance and safety of initial high-dose therapy.

Large initial doses of amiodarone hydrochloride for the treatment of ventricular arrhythmias refractory to conventional therapy were demonstrated to shorten the time to achieve control of the arrhythmia. As compared with a lower-dose regimen, the mean time to achieve partial control (suppression of ventricular tachycardia) was 10.6 +/- 5.2 days in the highest-dose group (group C), 9.5 +/- 6.4 days in the medium-dose group (group B), and 16.9 +/- 9.1 days in the lowest-dose group (group A). Complete control (suppression of virtually all ventricular ectopy) was similarly earlier in groups B and C (16.1 +/- 7.5 days and 16.0 +/- 11.3 days, respectively) as compared with group A (31.0 +/- 10.1 days). The final mean dose for long-term treatment was independent of the initial dose schedule (551 +/- 245 mg/day; range, 200 to 1,200 mg/day). The large doses were shown to be well tolerated and without serious side effects.

Amiodarone neuropathy.

Amiodarone, a drug used to treat refractory cardiac arrhythmias, produced a peripheral neuropathy in 5 of 50 cases (10%). Although the neuropathy may be severe, it tends to improve with lowering of the dosage or discontinuation of the medication.

Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic drug.

Six patients are presented who developed pulmonary infiltrates of undetermined origin while being treated for severe ventricular arrhythmias with amiodarone hydrochloride. Biopsy material was available in four patients and revealed interstitial or alveolar fibrosis and pneumonitis. Four patients recovered and two died of severe cardiopulmonary decompensation; all of the patients who recovered received corticosteroid therapy. Pulmonary fibrosis is a previously unreported complication of amiodarone therapy.