Philip J. Podrid

Use of the Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) To Assist with Triage of Patients with Chest Pain or Other Symptoms Suggestive of Acute Cardiac Ischemia: A Multicenter, Controlled Clinical Trial

More than half of emergency department diagnoses of acute cardiac ischemia (acute myocardial infarction or unstable angina pectoris) prove to be incorrect [1], leading to approximately 2 million unnecessary hospitalizations associated with

Amiodarone : reevaluation of an old drug

8 billion in costs annually in the United States [2]. Underdiagnosis of acute ischemia also occurs: Approximately 2% of emergency department patients with acute infarction are sent home [3, 4]. Unnecessary hospitalization for patients incorrectly presumed to have acute ischemia must be reduced without increasing inadvertent discharges of those with acute ischemia [5, 6]. To address this problem, we developed an acute cardiac ischemia predictive instrument to provide real-time guidance for triage decisions in the emergency department [1]. Programmed initially into a hand-held calculator, a logistic regression formula computed a patients probability (0% to 100%) of having acute ischemia on the basis of seven yes/no questions, including the presence of chest pain, chest pain as the chief symptom, a history of heart attack or nitroglycerine use, and electrocardiogram ST-segment or T-wave abnormalities. In a 2300-patient controlled clinical trial done in urban and rural hospitals in 1980-1981, providing patients probability values of acute ischemia to emergency department physicians improved triage decisions: Admissions to the coronary care unit (CCU) for patients without acute ischemia were reduced by 30% and missed cases of acute ischemia did not increase [1]. Unfortunately, the calculator-based instrument was not user-friendly for busy emergency department physicians and found limited use. In addition, it required physician interpretation of the ST segment and T waves, which may be incorrect 25% of the time [7], introducing error into predictions. To address these issues, a new version of the instrument was developed for incorporation into conventional computerized electrocardiograph [8-12]. It was designed to compute the probability value either by using data obtained during real-time emergency department care or retrospective review; thus, we called it an acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) [8, 13]. This was accomplished primarily by replacing the variables from the medical history with age, sex, and the presence of Q waves on electrocardiography. More detailed data on ST and T waves were also added. Diagnostic performance was equivalent to that of the original version, and no further variables were needed. Of note, classic long-term coronary risk factors, such as hypercholesterolemia and smoking, were not important predictors of acute ischemia in the emergency department compared with the variables used in ACI-TIPI [8, 14]. To acquire the ACI-TIPI probability in clinical use, the user enters the patients age and sex and indicates whether chest or left arm pain is the primary symptom; the electrocardiograph then directly measures the waveforms and computes and prints the probability of acute ischemia on the electrocardiogram header for the physicians immediate use (Figure 1). Figure 1. Example of an acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) electrocardiogram printed by conventional electrocardiograph for the trial. We report the results of a clinical trial to test the effect of electrocardiogram-based ACI-TIPI on emergency department triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia. We sought to determine whether its use would reduce unnecessary hospital and CCU admission for emergency department patients without cardiac ischemic disease or with stable angina pectoris while not reducing hospitalization of emergency department patients with acute ischemia (unstable angina or acute infarction). Because our previous work showed that the bed capacity of the hospital CCU influences emergency department triage [15] and that the effects of ACI-TIPI vary with the training level of residents [9], we hypothesized that the effect of ACI-TIPI would differ according to the bed capacities of CCUs and physician training status. Thus, we included hospitals with a wide range of CCU bed capacities and emergency department training programs. Methods Sites The study was conducted at 10 hospitals, including public, private, community, and tertiary hospitals with urban, suburban, and semi-rural catchment areas (Baystate Medical Center [Springfield, Massachusetts]; Boston City Hospital, Boston University Medical Center, and New England Medical Center [Boston, Massachusetts]; Medical College of Virginia [Richmond, Virginia]; Medical College of Wisconsin [Milwaukee, Wisconsin]; Newton-Wellesley Hospital [Newton, Massachusetts]; Rhode Island Hospital [Providence, Rhode Island]; University of Cincinnati Medical Center [Cincinnati, Ohio]; and University of North Carolina Hospitals [Chapel Hill, North Carolina]). All emergency departments had internal medicine residents; four had emergency medicine residents. Patients We included all consenting emergency department patients who 1) were at least 30 years of age or at least 18 years of age if they were suspected of using or were reported to have used cocaine recently and 2) had a chief symptom of chest, left arm, jaw, or epigastric pain or discomfort; shortness of breath; dizziness; palpitations; or other symptoms suggestive of acute ischemia. Intervention The ACI-TIPI was installed in each emergency departments native brand electrocardiographs by using software and necessary equipment upgrades provided by the manufacturer. Both brands used (Hewlett-Packard [Palo Alto, California] and Marquette [Milwaukee, Wisconsin]) generated equivalent predictions in the same format (Figure 1). Manufacturers had no input in the design or conduct of the study, data analysis, or reporting of results. The trial was carried out over 7 alternating months of control and intervention periods starting in May 1993. On presentation to the emergency department, each patients ACI-TIPI probability of acute ischemia was automatically computed by the electrocardiograph. During intervention periods, the probability was automatically printed on the electrocardiogram header, with an indication that it was to supplement, not replace physician judgment, along with the standard electrocardiogram interpretive header text. During control periods, only the standard header text was printed. Data Collection Sociodemographic information, initial and follow-up clinical features, electrocardiographic information, creatine kinase-MB test results, training level and supervision of the triaging physician, and hospital bed capacities were recorded at presentation to the emergency department, during hospitalization, and at the 30-day follow-up. The follow-up rate for data needed to assign confirmed true diagnoses, including those for patients who were not hospitalized, was 99%. The ACI-TIPI electrocardiograph allowed real-time acquisition of the following variables: age, sex, presence of chest or left arm pain, a chief symptom of chest or left arm pain, pathologic Q waves, and the presence and degree of ST-segment elevation or depression and T-wave elevation or inversion [9, 10]. Data Analysis Confirmed diagnoses were assigned by site physicians (who were blinded to study group assignment) on the basis of presentation and clinical course, initial and follow-up electrocardiograms, and creatine kinase-MB test results by using World Health Organization criteria [16]. Angina severity was classified by Canadian Cardiovascular Society classification criteria [17] and time since angina onset or pattern change. By using an iterative modified Delphi process based on the practices and opinions of study site emergency physicians, cardiologists, and other experts, we defined the following diagnostic groups for analysis a priori: 1) patients with acute cardiac ischemia [acute infarction or unstable angina], who, it was agreed, should be admitted to cardiac telemetry units or CCUs; 2) patients with stable angina pectoris [Canadian Cardiovascular Society classes 1 or 2 or class 3 without a new or changed anginal pattern in at least 4 days] who, clinicians felt, could be safely triaged home for outpatient follow-up; and 3) patients without cardiac ischemia, who did not require hospitalization. For analysis, study hospitals were divided into groups according to the pattern of relative CCU bed capacities. Five hospitals with low-capacity telemetry units (comparatively high-capacity CCUs) had cardiac telemetry unit-to-CCU bed ratios of 2 to 1 or less. Five hospitals with high-capacity telemetry units (low-capacity CCUs) had telemetry-to-CCU bed ratios at least double the ratios of hospitals with low-capacity telemetry units. A priori, we elected to consider physicians who signed the official medical record as the responsible physicians. Thus, each patient was classified as having been triaged by an attending physician (single signature), a resident supervised by an attending (both signatures), or an unsupervised resident (single signature). Statistical Analysis Baseline comparisons of patient characteristics between control and intervention months were done by using t-tests for continuous variables and chi-square tests for categorical variables, including emergency department triage dispositions. Using Cochran-Mantel-Haenszel adjustments for individual hospitals did not change significance levels. When few patients were sent to wards ( 3%), emergency department dispositions to ward and telemetry units were combined for statistical testing in the tables (but were kept separate for presentation in the text). Apparent discrepancies between emergency department triage disposition rates and computer disposition-specific changes are due to the effects of rounding. The possibility of changes over the course of the trial in differences between control and intervention periods (learning) was checked by testing for

Side effects from amiodarone

In most patients, therapy for arrhythmia involves the administration of antiarrhythmic agents, but recent developments have mandated a reassessment of these agents. Several studies have highlighted the potential risks of pharmacologic therapy, and, with the availability of new methods of treatment, disenchantment with antiarrhythmic drugs has been growing. Despite this concern, pharmacologic therapy has an important role in the management of arrhythmia, and the benefits and risks of this therapy must be considered for the individual patient. Over the past few years, emerging data have created much concern about the potential hazards of antiarrhythmic drugs. The Cardiac Arrhythmic Suppression Trial (CAST) [1, 2] reported the harmful effects of flecainide, encainide, and moricizine in patients with ventricular premature beats who had had myocardial infarction. Compared with placebo, flecainide, encainide, and moricizine were associated with increased mortality from sudden cardiac death. In an earlier, noncontrolled trial [3], mexiletine was also associated with a trend toward increased mortality. In meta-analyses of studies of quinidine as therapy for nonsustained ventricular tachycardia and prevention of atrial fibrillation [4, 5], drug therapy was associated with increased mortality when compared with placebo or with no therapy. Such studies have resulted in growing therapeutic nihilism on the part of many physicians. In contrast to many antiarrhythmic drugs, amiodarone has been reported to be effective in several patient populations and is not associated with increased mortality. Although in the United States amiodarone is currently indicated only for life-threatening ventricular arrhythmias refractory to other agents, it is highly effective for the suppression and prevention of other arrhythmias [6-8]. Of concern, however, has been the toxicity associated with this agent. Many patients have some side effects, but these are generally mild; serious toxicity involving the liver, lungs, and thyroid is infrequent and can usually be predicted with close monitoring and careful follow-up. Unlike the other antiarrhythmic agents, amiodarone administered orally has resulted in only isolated reports of arrhythmia aggravation [9, 10]. This aggravation has usually occurred in patients with concomitant hypokalemia or in patients receiving another antiarrhythmic agent, particularly a class IA drug. No studies involving patients with arrhythmia have shown amiodarone to be associated with increased mortality. Therefore, in view of the growing concern about class I antiarrhythmic drugs, it seems reasonable that the benefits, risks, and therapeutic role of amiodarone be reassessed. Unfortunately, few well-controlled trials have compared amiodarone with placebo, other drugs, or nonpharmacologic therapy. Controlled trials are now in progress and should provide important data. However, in this paper, I review available data about the pharmacology, electrophysiology, and toxicity of amiodarone and discuss the use of this agent in the treatment of atrial fibrillation and flutter; the treatment of nonsustained ventricular tachycardia in patients with cardiomyopathy and congestive heart failure; the treatment of patients who have recently had myocardial infarction; and the prevention of recurrent sustained ventricular tachycardia and ventricular fibrillation. Electrophysiologic Actions and Pharmacologic Properties Amiodarone is a unique and complex drug that was originally used as an antianginal agent because it is a potent vasodilator and significantly slows heart rate [11]. Although it is still used for this purpose, especially in patients with refractory angina who are not candidates for revascularization [12], amiodarone has gained wider use as an antiarrhythmic agent [13] because of its various pharmacologic actions on the heart [14]. Its most important direct electrophysiologic effect is prolongation of the action potential duration and repolarization time; this prolongation results from inhibition of the potassium ion fluxes that normally occur during phases 2 and 3 of the action potential [15] and from prolongation of the refractory periods. These actions represent the class III activity of amiodarone and occur in all cardiac tissue. The increase in the duration of repolarization and refractoriness reduces membrane excitability; this reduction represents the antifibrillatory property of amiodarone. Most class III antiarrhythmic drugs have a property called reverse-use dependency, which causes the action potential duration (QT interval or repolarization time) to become progressively shorter as heart rate increases. However, amiodarone does not have this property; the prolongation of repolarization time that amiodarone causes persists at higher heart rates [16]. Amiodarone is also a weak sodium channel blocker and, as a result of its class I antiarrhythmic activity, slows the upstroke velocity of phase 0 of the action potential [17]. This reduces the rate of membrane depolarization and impulse conduction. Amiodarone also directly depresses the automaticity of the sinus and atrioventricular nodes. In addition to these direct antiarrhythmic effects, amiodarone has several important actions, including -blockade, that indirectly affect the electrophysiologic properties of the myocardium. Unlike blockade using the standard -blocking agents, amiodarones blockade of the -adrenergic receptors is noncompetitive and results from inhibition of adenylate cyclase formation and from a reduction in the number of -adrenergic receptors [18]. Amiodarone also shows noncompetitive -blocking activity and inhibits the slow inward calcium-ion current. Lastly, it is possible that some antiarrhythmic actions of amiodarone result from its antithyroid effect: The drug interferes with thyroid metabolism and with the effects of thyroxin on the heart [19]. It is important to note that amiodarone contains two iodine molecules and that 37.5% of the drugs weight is iodine (75 mg iodine/200 mg amiodarone). Hemodynamic Effects Because of its numerous pharmacologic actions, amiodarone causes many important hemodynamic effects [14, 20]. As a result of its direct effect on smooth muscle and its calcium channel and -adrenergic receptor blockade, amiodarone dilates coronary arteries and increases coronary blood supply. It also causes peripheral arterial vasodilation and decreases systematic blood pressure and afterload. Amiodarone has mild direct negatively inotropic actions and reduces the force of myocardial contraction; however, this is offset by the drugs peripheral vascular effects, primarily afterload reduction, and stroke volume and cardiac output are generally maintained [20]. As previously indicated, the drug slows the sinus rate through direct effects on automaticity, antisympathetic action, and inhibition of slow inward calcium-ion currents. The hemodynamic properties of amiodarone make it understandable that the drug was first used as an antianginal agent. Pharmacokinetics The gastrointestinal absorption of amiodarone is slow and incomplete: A peak serum level is achieved 4 to 7 hours after an oral dose is received [21]. Only 50% of the administered dose is bioavailable because of first-pass intestinal mucosal and hepatic metabolism as well as incomplete absorption. Amiodarone is highly protein- and lipid-bound and is widely distributed throughout all adipose tissue [22]. As a result of the drugs avid affinity for adipose tissue, the estimated volume of distribution is 50 L, and approximately 15 g are necessary to saturate these large body stores. For these reasons, a long and variable loading period is necessary before antiarrhythmic activity is apparent. Clearance of amiodarone involves deiodination, but the major route of elimination is by hepatic metabolism to one principal metabolite, desethyl-amiodarone, which has antiarrhythmic activity equivalent to that of the parent drug [23]. It has been reported that a serum concentration of at least 1 to 2 g/mL is necessary for drug efficacy, but there is wide interpatient variability in the dose-concentration relation and in levels associated with efficacy or toxicity. Therefore, amiodarone levels in the blood have limited clinical usefulness. The elimination half-life of amiodarone is also highly variable but long, ranging from 16 to 180 days (mean, 52 days), because of the drugs extensive storage and avid binding to poorly perfused adipose tissue [22]. Because of the unique pharmacokinetic properties of amiodarone, the onset of the drugs action is delayed and may not be apparent for as long as 3 months. When administered orally, a loading dose of the drug is required. The dose used depends on the arrhythmia being treated, the need to achieve efficacy more quickly, and the occurrence of side effects, some of which are associated with higher doses. For the treatment of ventricular tachyarrhythmias, a recommended dosing schedule is 1200 to 1800 mg/d for 1 to 2 weeks, then 800 mg/d for 2 to 4 weeks, then 600 mg/d for 1 month, and 200 to 400 mg/d thereafter. For the treatment of supraventricular arrhythmia, the initial dose is 600 to 800 mg/d for 4 weeks, 400 mg/d for 2 to 4 weeks, and 200 mg/d thereafter. However, the actual duration of loading and the optimal dose used vary for individual patients and depend on efficacy and toxicity. Although not yet approved for use in the United States, an intravenous preparation of amiodarone may be helpful for the acute management of life-threatening ventricular arrhythmias, especially when other intravenous therapies have failed [24, 25]. The drug is administered as a rapid infusion of 5 mg/kg body weight over 15 to 30 minutes and is followed by 1 g/24 h thereafter. Although there are no absolute guidelines for predicting the onset of drug activity or the time required for evaluating its effect, the onset of typical electrocardiographic changes associated with amio

Prognosis of Medically Treated Patients with Coronary-Artery Disease with Profound ST-Segment Depression during Exercise Testing

Amiodarone causes many side effects involving all organ systems. Although most of the side effects are mild and do not limit the use of the drug, there are several that are serious. Since many of these toxic reactions develop only after a prolonged period of therapy, careful follow-up on a regular basis is essential.

Potassium and ventricular arrhythmias

Reproducible and profound (greater than 2 mm) ST-segment depression during exercise testing in patients with coronary heart disease is associated with multivessel involvement. In these patients, coronary-artery bypass surgery has been recommended even when symptoms are absent. However, there are few long-term follow-up data regarding the prognosis when such patients are treated medically. Among 212 men with coronary-artery disease in whom profound ST-segment depression could be reproduced with exercise, 142 who had no other type of heart disease and were not receiving digitalis drugs had a mean ST-segment depression of 2.9 mm. Follow-up has lasted an average of 59 months: 11 patients have died (annual mortality, 1.4 per cent), and nine have had bypass operations (1.3 per cent per year). Survival correlated with exercise tolerance but not with degree of ST depression, peak heart rate, or peak blood pressure during exercise. We conclude that such ST-segment depression is not associated with a poor prognosis. There is rarely a need to resort to cardiac surgery; medical management is highly successful and associated with a low mortality.

Propafenone: A new agent for ventricular arrhythmia

Potassium is a major determinant of the electrophysiologic properties of the myocardial membrane, and it plays an important role in the occurrence of arrhythmia. Hypokalemia has been associated with an increased frequency of ventricular premature complexes (VPCs) in some studies of hypertensive patients treated with diuretics, but other studies have failed to confirm any association. Studies involving patients with an acute myocardial infarction have also provided conflicting data about the association between hypokalemia and VPCs. Whereas the role of potassium in the genesis of simple VPCs remains uncertain, animal and clinical studies have demonstrated a strong relation between hypokalemia and the occurrence of sustained ventricular tachycardia and ventricular fibrillation during acute ischemic states. Hypokalemia may also affect the action of antiarrhythmic drugs by altering the electrophysiologic properties of the myocardium, potentially negating some of the antiarrhythmic activity of these agents. Although diuretic use is the most frequent cause of hypokalemia, epinephrine can also lower serum potassium as a result of stimulation of the beta 2 adrenoreceptor. This mechanism may, in part, explain the ability of beta blockers to prevent sudden death in patients with a recent myocardial infarction.

Resuscitation in the Elderly: A Blessing or a Curse?

Propafenone, a new antiarrhythmic agent, was utilized in 30 patients with diverse heart disease who presented with sustained hemodynamically unstable ventricular arrhythmia. Drug efficacy was judged by means of ambulatory electrocardiographic monitoring and exercise testing. Nine patients additionally had invasive electrophysiologic studies. Seventeen patients (57%) responded to therapy as judged by monitoring and 21 patients (70%) responded to therapy as judged by exercise testing. When both methods were considered, 16 patients (53%) responded. The acute drug test predicted the result of maintenance therapy in 91% of patients. Seven of nine patients who had electrophysiologic testing responded based on this technique, and in all cases the results were concordant with the noninvasive evaluation. Serum blood levels did not correlate with antiarrhythmic effect. In patients with myocardial impairment, echocardiographic assessment of left ventricular function indicated a decrease in ejection fraction during propafenone therapy (32 versus 24%, p less than 0.05), while no change was observed in patients with normal left ventricular function. Side effects occurred in nine patients and included exacerbation of congestive heart failure, development of conduction abnormalities and aggravation of arrhythmia, each occurring in two patients. Ten patients who continued on long-term propafenone therapy for an average of 10 months (range 3 to 13) have remained free of arrhythmia and side effects. Propafenone needs to be employed with caution in patients with congestive heart failure or evidence of conduction system disease.

Ventricular arrhythmia in congestive heart failure

Excerpt Sudden cardiac death accounts for 400 000 to 600 000 deaths each year in the United States, and these numbers have not improved despite the many advances in cardiology. Unfortunately, most ...

The role of exercise testing in evaluation of arrhythmias

The importance of ventricular arrhythmia is based on its association with sudden death. In certain groups of patients, ventricular arrhythmia--primarily runs of nonsustained ventricular tachycardia (NSVT)--is associated with an increased risk for sudden death. Although this relationship has been most often reported in patients with recent myocardial infarction, it has also been recognized in patients with dilated cardiomyopathy, regardless of etiology. Therefore, ventricular arrhythmia is common in patients with CHF due to cardiomyopathy. A number of studies have reported that 70-95% of patients with cardiomyopathy and congestive heart failure (CHF) have frequent ventricular premature beats, and 40-80% will manifest runs of NSVT. Many factors are responsible for ventricular arrhythmia in such patients, including structural abnormalities, electrolyte imbalance, hemodynamic impairment, activation of neurohormonal mechanisms, and pharmacologic therapy. Many studies have reported a high yearly mortality in patients with cardiomyopathy and CHF; greater than 40% of deaths are sudden, most often the result of sustained ventricular tachyarrhythmia. Most studies have noted an association between presence (and frequency) of NSVT and risk of sudden cardiac death in these patients. Unfortunately, other techniques--such as the signal-averaged electrocardiogram and electrophysiologic testing--are not helpful in identifying the individual at risk. Although several drug interventions will reduce mortality from progressive CHF, these drugs have not been shown to reduce sudden death and, indeed, have a variable effect on ventricular arrhythmia. Although NSVT is a marker for increased risk for sudden death, it is uncertain if antiarrhythmic drugs will prevent this outcome. Antiarrhythmic drugs have not been shown to be effective for preventing sudden death, although there are as yet no well-controlled randomized trials. Several studies suggest that amiodarone and beta blockers are beneficial, but this requires confirmation. For patients who have been resuscitated following an episode of sudden death due to a sustained ventricular tachyarrhythmia, antiarrhythmic therapy guided by invasive and noninvasive techniques appears to reduce risk of recurrent arrhythmia. However, the response rate to antiarrhythmic agents is low and side effects are common in patients with CHF. Especially important is the increased risk of precipitating CHF and aggravating the arrhythmia being treated. For many such patients who have had serious ventricular tachyarrhythmia, the automatic implantable cardioverter defibrillator may prove a better option. Other drugs used for management of CHF reduce overall mortality, but not risk of sudden death.

Safety and tolerability of long-term Propafenone therapy for supraventricular tachyarrhythmias

Exercise testing has been widely applied for the evaluation of patients with coronary artery disease. The principles underlying its use for this indication make it a useful adjunctive technique, when combined with ambulatory monitoring, to diagnose arrhythmias and monitor antiarrhythmic drug therapy. During exercise, there is a withdrawal of vagal tone and a marked increase in circulating catecholamines and sympathetic inputs to the heart. These changes may directly cause arrhythmias (e.g., catecholamines can enhance automaticity and delayed afterpotentials and can shorten myocardial conduction time and refractory periods). However, they also augment myocardial oxygen demands by increasing myocardial inotropy, heart rate and blood pressure. Such changes may cause ischemia in patients with heart disease, which is a powerful stimulus for arrhythmia, or lead to dysfunction in left ventricular contraction and increased myocardial wall stress, factors that also may precipitate arrhythmia. In approximately 10% of patients with a history of serious arrhythmia, exercise represents the only means for exposing arrhythmia. Importantly, this technique is useful for evaluating the effect of antiarrhythmic drugs. These agents work by reducing membrane automaticity, slowing impulse conduction through the myocardium and prolonging membrane refractoriness. In contrast, catecholamines, which are secreted in response to exercise, have the opposite effect. Thus, exercise may negate the important effects of the antiarrhythmic drugs. Additionally, exercise testing may expose potentially serious toxic drug reactions that may not be obvious at rest. These include conduction abnormalities, negative inotropic effects, congestive heart failure and aggravation of arrhythmia. Although the presence and frequency of arrhythmia with exercise is highly variable in patients with benign arrhythmia, results are more consistent in patients with a history of serious arrhythmia. If arrhythmia is reproducibly provoked with exercise, this technique can be used to judge drug effect. Thus, exercise testing is an important, reliable and helpful technique for exposing arrhythmia, evaluating drug efficacy and identifying potentially serious toxic drug effects.