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.

Psychiatric aspects of congestive heart failure: implications for consulting psychiatrists.

Abnormalities of mental function are common problems in patients with congestive heart failure, a problem that is often referred to the consulting psychiatrist. These abnormalities become more frequent and more serious as failure of the heart progresses and they can exhibit a wide variety of manifestations. Cardiac output and cerebral blood flow are preserved due to compensatory mechanisms in mild heart failure but can be severely compromised in advanced failure. Drugs used to treat heart failure, especially digitalis, can produce a wide variety of mental aberrations including delirium, usually when these drugs are used in excess. Diuretics can produce electrolyte abnormalities resulting in mental derangements and vasodilator therapy can produce hypotension. Psychotropic drugs are well recognized as having significant cardiovascular effects that need to be considered when these agents are applied to the cardiac patient. Antidepressant and antipsychotic drugs have anticholinergic, antiadrenergic and quinidine-like effects that can produce further cardiac decompensation in heart failure. Antidepressants are generally well tolerated except when toxic levels occur or in the most extremely compromised cardiac patients. Monoamine oxidase inhibitors should be used only in highly reliable patients to avoid the acute hypertensive crises that are well known to occur with these agents. Antipsychotic drugs with limited cardiovascular side effects can be used effectively and safely but care must be taken to avoid toxic levels which could produce excess hypotension or lethal arrhythmias. Lithium can also be used in heart failure if patients are effectively monitored to avoid toxic levels which could occur due to reduction in renal function, use of diuretics or imposition of a low sodium chloride diet. Evaluation and management of patients with mental symptoms and heart failure provides a strong challenge for the consulting psychiatrist.

Myocardial blood flow during exercise in dogs with left ventricular hypertrophy produced by aortic banding and perinephritic hypertension.

This study tested the hypothesis that for similar degrees of left ventricular hypertrophy, subendocardial blood flow would be facilitated by the increased diastolic coronary perfusion pressure associated with arterial hypertension, as compared with hypertrophy produced by banding the ascending aorta. Left ventricular hypertrophy was produced with perinephritic hypertension in seven adult dogs and by banding the ascending aorta in nine adult dogs. Left ventricular/body weight ratios were 6.15 +/- 0.59 g/kg in the hypertensive animals and 6.87 +/- 0.47 g/kg in dogs with aortic banding, as compared with 4.23 +/- 0.23 g/kg in seven normal dogs (p less than .01). Studies were performed at rest and during two stages of treadmill exercise to achieve heart rates of 195 and 260 beats/min. Diastolic aortic pressure was increased in animals with hypertension but not in dogs with aortic banding. Systolic ejection period was prolonged in dogs with aortic banding but not in hypertensive dogs. Mean blood flow per gram of myocardium measured with microspheres was similar at rest and during light exercise in all three groups of animals, whereas during heavy exercise blood flow was significantly greater than normal in both groups with hypertrophy. In normal dogs subendocardial/subepicardial (endo/epi) flow ratios did not change significantly during exercise. In both groups with hypertrophy, endo/epi ratios were normal at rest but decreased significantly during exercise. During heavy exercise the endo/epi ratio decreased to 0.73 +/- 0.08 in dogs with aortic banding as compared with 1.07 +/- 0.12 in hypertensive dogs (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

The ST segment/heart rate slope as a predictor of coronary artery disease: comparison with quantitative thallium imaging and conventional ST segment criteria.

The ST segment shift relative to exercise-induced increments in heart rate, the ST/heart rate slope (ST/HR slope), has been proposed as a more accurate ECG criterion for diagnosing significant coronary artery disease (CAD). Its clinical utility, with the use of a standard treadmill protocol, was compared with quantitative stress thallium (TI) and standard treadmill criteria in 64 unselected patients who underwent coronary angiography. The overall diagnostic accuracy of the ST/HR slope was an improvement over TI and conventional ST criteria (81%, 67%, and 69%). For patients failing to reach 85% of their age-predicted maximal heart rate, its diagnostic accuracy was comparable with TI (77% and 74%). Its sensitivity in patients without prior myocardial infarctions was equivalent to that of thallium (91% and 95%). The ST/HR slope was directly related to the angiographic severity (Gensini score) of CAD in patients without a prior infarction (r = 0.61, p less than 0.001). The ST/HR slope was an improved ECG criterion for diagnosing CAD and compared favorably with TI imaging.

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.

Ventricular arrhythmias during treatment for acute asthma.

A double-blind, randomized study was performed to determine the occurrence of ventricular arrhythmias in acute asthma patients treated with epinephrine, aminophylline, or both in combination. Sixty patients were studied with Holter monitoring during the 90-minute study period. There was no statistical difference among the study groups in frequency or grade of ventricular arrhythmia. Combination treatment of acute asthma with these drugs is as safe as treatment with either alone.

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.

Abnormalities in myocardial perfusion during tachycardia in dogs with left ventricular hypertrophy: metabolic evidence for myocardial ischemia.

This study tested the hypothesis that in the chronically hypertrophied left ventricle pacing stress may cause abnormalities of perfusion that result in myocardial ischemia. Left ventricular hypertrophy (LVH) was produced by banding the ascending aorta of 10 dogs at 6 weeks of age, and studies were carried out after the animals had reached adulthood and when mean left ventricular/body weight ratio was 74% greater than in eight control dogs. Myocardial blood flow was measured with microspheres during pacing at 100, 200, and 250 beats/min, while aortic and coronary sinus blood samples were obtained for determination of concentrations of lactate and the adenosine metabolites inosine and hypoxanthine. In the control dogs, increasing heart rates were associated with an increase in mean myocardial blood flow while subendocardial flow was maintained at a level equal to or greater than subepicardial flow. Myocardial lactate uptake ranged from +60% to -5%, and adenosine metabolites were not detected in coronary sinus blood (less than 0.5 microM/l). In four dogs that underwent aortic banding no production of lactate or adenosine metabolites was observed at any heart rate; in these animals subendocardial flow was maintained at a level equal to or greater than subepicardial flow at all pacing rates. The remaining six dogs with LVH demonstrated net lactate production significantly greater than control during pacing at 250 beats/min; five of these six animals also produced adenosine metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation of heart rate and shortening fraction to echocardiographic indexes of left ventricular relaxation in normal subjects.

To determine the relation of heart rate and systolic function to echocardiographically derived indexes of left ventricular relaxation, M-mode echocardiograms of the left ventricle and mitral valve with a simultaneous phonocardiogram were recorded at rest from 28 normal men. The effects of altering the inotropic state and ventricular loading conditions were examined during isometric handgrip exercise and the Valsalva maneuver in a subset of 15 men. The left ventricular endocardial echocardiograms were digitized to provide a display of left ventricular internal dimension and its first derivative (dD/dt). The time course of relaxation, defined as the interval from left ventricular minimal systolic dimension to the point when the rate of change of dimension (dD/dt) decreased to 50% of peak, was directly related to the RR interval (r = 0.64, p less than 0.0001) in the entire group, and this relation remained throughout the interventions. The slopes of the regression lines of relaxation time (RT) and electromechanical systole (QS2) on the RR interval were similar. Diastolic time decreased proportionately more than relaxation time as the RR interval decreased, so that the proportion of diastole occupied by the relaxation time varied with cycle length. Peak diastolic dD/dt, normalized for variations in end-diastolic dimensions [( dD/dt]/D), was directly related to left ventricular shortening fraction (r = 0.71 p less than 0.0001) and this relation remained during isometric grip. There was no correlation between the heart rate at rest and (dD/dt)/D over the range of 44 to 99 beats/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial lactate and adenosine metabolite production as indicators of exercise-induced myocardial ischemia in the dog.

To determine the value of lactate and the adenosine metabolites inosine and hypoxanthine as indicators of myocardial ischemia, we measured the levels of these metabolites in arterial and coronary sinus blood of nine chronically instrumented dogs subjected to exercise stress before and during reversible circumflex coronary artery occlusion. The degree of circumflex bed hypoperfusion was measured by 15-mu microspheres and the reduction in circumflex coronary flow was measured with a proximal flow probe. Adenosine metabolites, although below the level of accurate detection in our laboratory in arterial blood (i.e., 0.5 microM/l), were detected in coronary sinus blood (range 2.7--18.7 microM/l) in 26 of 33 studies with partial circumflex occlusion when circumflex flow was reduced to less than 80% of that seen during exercise without occlusion and when only subendocardial perfusion was reduced. Global left ventricular flow and transmural flow in nonischemic beds did not correlate with positive studies. Myocardial lactate extraction was a less accurate test for determining circumflex bed hypoperfusion. Thus, myocardial production of adenosine metabolites is a sensitive qualitative test of exercise-induced ischemia responding to a modest fall in coronary flow when only subendocardial hypoperfusion is present.

Effect of heart rate on myocardial blood flow in dogs with left ventricular hypertrophy.

Because of the previous suggestion that subendocardial perfusion may be inadequate in the hypertrophied heart, this study was carried out to examine the response of transmural myocardial blood flow to pacing induced tachycardia in dogs with chronic left ventricular hypertrophy. Myocardial hypertrophy, produced by banding the ascending aorta of puppies at 5-6 wk of age, resulted in an 87% average increase in relative left ventricular mass compared with the control dogs. Myocardial blood flow was examined during ventricular pacing at heart rates of 100, 200, and 250 beats/min using radionuclide-labeled microspheres. Mean blood flow per unit myocardial mass was similar in the two groups of dogs at a heart rate of 100 beats/min and increased regularly during pacing in both groups of animals. Increasing heart rates did not change the transmural pattern of myocardial blood flow in the normal dogs, but in the animals with left ventricular hypertrophy pacing at 250 beats/min resulted in a significant redistribution of perfusion away from the subendocardium, with the ratio of subendocardial/subepicardial blood flow falling from 1.03 +/- 0.08 at 100 beats/min to 0.83 +/0 0.06 at 250 beats/min (P < 0.01). This redistribution of blood flow away from the subendocardium was especially marked in the regions encompassing the papillary muscles and the intervening left ventricular lateral wall.