Louis Rakita

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addition, a case report is presented of a patient who developed pulmonary changes that disappeared when amiodarone was withdrawn and did not recur when amiodarone was reinstituted.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 patients 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.

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.

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: 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)

The acute and chronic effects of phlebotomy on general hemodynamics and pulmonary functions of patients with secondary polycythemia associated with pulmonary emphysema

Abstract 1.1. Hemodynamic and pulmonary function studies were evaluated in 15 patients with secondary polycythemia associated with chronic pulmonary emphysema. 2.2. The studies were made before and after acute venesection and again after sufficient venesection to maintain hematocrits at nearly normal levels for periods of 5 to 6 weeks. 3.3. Significant decreases in hematocrit, right atrial and right ventricular systolic, end-diastolic, and mean pressures, and significant increases in arterial oxygen saturation and tension, oxygen consumption, and arteriovenous oxygen difference were noted in measurements carried out 1 hour after the initial phlebotomy. 4.4. In the total group, no changes occurred in pulmonary function studies after acute phlebotomy or repeat phlebotomies, or in hemodynamic studies after repeat phlebotomies. 5.5. In patients with high end-diastolic right ventricular pressures at the initial catheterizations, acute phlebotomy was followed by decreases in the residual lung volume and functional residual capacity, although these had increased to the control values after 6 weeks. 6.6. It is possible that the observed changes in O 2 gas studies and residual lung volumes may be related to changes in intrapulmonary blood volume or flow. 7.7. All of the changes observed after repeated phlebotomies can be explained by the mechanical removal of red blood cells. 8.8. There is no indication that polycythemia, of itself, is detrimental to the hemodynamic or pulmonary function status of these patients when heart failure has not supervened. 9.9. Venesection has a therapeutic role in the management of patients with secondary polycythemia associated with chronic pulmonary emphysema. Immediate phlebotomy should be helpful in controlling heart failure, and repeat phlebotomies, although not altering the hemodynamic or pulmonary function status of these patients, may be indicated because of the reduction in the viscosity, and, therefore, presumably for the effect on the incidence of thromboembolic complications. It would appear that the utilization of repeated phlebotomies should be determined by the degree of polycythemia rather than by the pulmonary function status of the patient.

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.

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.

Acute Hemodynamic Effects of Hexamethonium in Normotensive Man

The effect of intravenous hexamethonium bromide was studied in 10 normotensive human subjects in the steady state. In the absence of over-all change in cardiac output, the variable decrease in arterial pressure is accounted for by decrease in calculated total peripheral resistance.

Hemodynamic response to supine exercise in patients with chest pain and normal coronary arteriograms

Abstract During the past year, the response to supine exercise was included in the hemodynamic evaluation of almost all patients referred to our laboratory because of chest pain. Seventeen of 58 patients with chest pain were found to have normal coronary arteriograms, normal resting intracardiac pressures, and a normal left ventriculogram. Nine of these 17 patients had an abnormal exercise response, as evidenced by a significant increase in the left ventricular end diastolic pressure. The degree of left ventricular dysfunction was minimal, since exercise cardiac output increased normally, stroke volume was maintained during exercise, and the calculated left ventricular end-diastolic volumes and ejection fractions were normal. Atypical chest pain was present in all but one subject, who had typical angina pectoris. In addition, the group shared features such as arrhythmias, dyspnea, and non-specific electrocardiographic abnormalities, which are common to all forms of cardiomyopathy. We suggest that this patient group may frequently be mislabeled as having no cardiac disorder when no further evaluation of cardiac function, other than resting intracardiac pressures and a left ventriculogram, is carried out.

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.