Prevalence of ischemic resting and stress electrocardiographic abnormalities and angina among 40- to 59-year-old men in selected U.S. and U.S.S.R. populations.

The prevalence of electrocardiographic (ECG) abnormalities and angina was investigated in 40- to 59-year-old men from two samples, one from a U.S.S.R. study in two locations and one from a U.S. study in nine locations. ECG abnormalities were defined by the Minnesota code and angina was defined by the Rose questionnaire. No differences were found in the prevalence of major Q waves and major or minor ischemia between the two samples, but differences were found in specific indicators of major ischemia. Major ischemic changes were more prevalent in older subjects in both samples. Estimated prevalence of angina was 50% less in the U.S. sample than in the U.S.S.R. sample, and this was consistent with the proportion of subjects excluded from the exercise test because of angina. In both samples, subjects with ECG abnormalities had higher systolic blood pressures. No difference in exercise test abnormalities was found between samples; however, more subjects with a history compatible with coronary artery disease were excluded from the U.S.S.R. sample.

Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose.

A rapid method for assessing the free digoxin concentration in the serum of digoxin-overdosed patients receiving treatment with digoxin-specific Fab fragments has been developed. For this method, a protein-free ultrafiltrate is prepared from the patient's serum, and the digoxin in the ultrafiltrate (free digoxin) is measured by fluorescence polarization immunoassay. Both the inaccuracies associated with measurements of total digoxin by immunoassay in the presence of Fab and the long turnaround time associated with measurements of free digoxin by equilibrium dialysis were avoided. Good correlation was observed between measurements of free digoxin by this ultrafiltration technique and by equilibrium dialysis. The ultrafiltration method was used to evaluate the concentrations of free digoxin in a digoxin-overdosed patient treated with Fab at our hospital. In retrospect, the results suggest that her hospital stay could have been shortened by a timely appreciation of her increased concentration of free digoxin. Using the ultrafiltration method, one can determine free digoxin concentrations quickly, conveniently, and accurately in the clinical laboratory. This procedure therefore should be a valuable aid in monitoring the efficacy and adequacy of Fab treatment.

Effect of positive end-expiratory pressure on right and left ventricular function in patients with the adult respiratory distress syndrome.

The predominant mechanism of the cardiac output reduction associated with positive end-expiratory pressure (PEEP) is unclear. Reported possibilities include decreased systemic venous return, increased pulmonary vascular resistance, or change in ventricular contractility. We investigated this question by studying 9 patients with the adult respiratory distress syndrome (ARDS) during PEEP application. We used an equilibrium radionuclide angiography method modified for improved right ventricular imaging to evaluate changes in left and right ventricular volume and contractility. Thermodilution cardiac output and stroke volume progressively declined (27 and 33% mean decrease, respectively) with increasing increments of PEEP. Right and left ventricular end diastolic counts, reflecting volume, also progressively diminished as PEEP increased (38 and 27% mean decrease in RV and LV counts, respectively; p less than 0.001 for both ventricles). A slight upward trend in ejection fraction was found for both ventricles. These findings support the concept that during PEEP application the reduction in cardiac output is due to biventricular reduction in blood volume. This biventricular volume reduction is compatible with either preload reduction to both ventricles because of impeded venous return or to change in ventricular configuration caused by external compression of both ventricles.

Specificity, sensitivity, and prevalence in the design of randomized trials: a univariate analysis.

The number of cases needed to conduct a randomized trial is related to the sensitivity and specificity of a measurement indicative of a condition, to the prevalence of the condition, to the expected benefit of therapy (or other basis for change), and to the statistical precision desired. Sample size calculations frequently ignore sensitivity and specificity (at least qualitatively) probably because no simple formula is provided in the literature. Such a formula is included here. As an example, the number of patients required for a randomized clinical trial was calculated for a clinical outcome (nonfatal myocardial infarction or coronary artery disease death) used to detect atherosclerotic heart disease and is compared to the sample sizes required for each of three noninvasive diagnostic studies (exercise ECG ST depression, exercise LVEF reduction, and thallium myocardial imaging) performed for the detection of atherosclerotic heart disease. We calculated that the sample size should be much smaller when these diagnostic studies are employed compared to the clinical outcome, thereby offering the potential for reduced cost and complexity of a randomized clinical trial.

Effect of amiodarone on ventricular function as measured by gated radionuclide angiography.

Myocardial size and contractility were measured by gated radionuclide ventriculography in 70 patients before and a mean of 66 days after beginning amiodarone therapy. The mean dose of amiodarone at the time of the second study was 481 mg. The mean left ventricular (LV) ejection fraction (EF) increased slightly, from 40% to 43% (p = 0.001). The mean right ventricular EF remained unchanged (38% to 39%, difference not significant [NS]). The LV end-diastolic volume (count-based method) increased by 9% (p = 0.01), but no change could be demonstrated for end-systolic volume (4%, NS). The LV stroke volume increased 19% (p = 0.001), but cardiac output remained unchanged (5%, NS) because the heart rate decreased by 9 beats/min (p = 0.001). The right ventricular end-diastolic volume increased by 12% (p = 0.01) and end-systolic volume increased by 11% (p = 0.03). Stroke volume increased by 18% (p = 0.005). There was no significant correlation between the change in LVEF and the pre-amiodarone LVEF, the time interval between studies, or with indexes of amiodarone effect (change in heart rate, QRS, QTc, TSH, amiodarone dosage). In 5 patients (7%), LVEF decreased significantly, requiring discontinuation of amiodarone therapy in 1 patient. At the time of the second study congestive heart failure was manifest in 19%, and there was a trend suggesting that congestive heart failure was more likely if the initial LVEF was less than or equal to 35% (p = 0.10). Thus, amiodarone may rarely adversely affect contractility, although myocardial contractility is typically unchanged. There is an associated small increase in the size of both ventricles.

Prospective evaluation of amiodarone pulmonary toxicity.

Reports of pulmonary infiltrates in patients taking amiodarone, initiated the study of 69 patients for pulmonary toxicity using serial chest roentgenograms (CXRs), pulmonary function tests (PFTs), and symptoms before and during therapy. Mean PFTs did not significantly change from their baseline normal values, but 10 percent of patients had a greater than or equal to 15 percent fall in total lung capacity, and 28 percent a greater than or equal to 15 percent fall in diffusion capacity (DCO) following treatment. Initial abnormalities in pulmonary function or CXR were predictive of risk of developing pulmonary toxicity. Degree of exposure to amiodarone (dose plus duration) correlated only weakly with development of pulmonary toxicity, which could occur in patients taking relatively small doses of the drug. Pulmonary complications of amiodarone are common, in most cases reversible, and often confused with congestive heart failure or pneumonia. Patients should be evaluated before treatment by assessing symptoms, CXRs, and DCO. Patients with initial abnormalities in these parameters, particularly both CXR and DCO abnormalities, should be considered for alternative therapy.

Ventricular fibrillation causes sudden death in Southeast Asian immigrants.

Young, male, Southeast Asian immigrants living in the United States have a high incidence of unexplained, sudden, nocturnal death. We report the cases of three patients, two Laotians and one Filipino, who were resuscitated and subsequently studied extensively. Each patient was having ventricular fibrillation when first examined by paramedics outside the hospital, and episodes of fibrillation recurred in the early hospital course. Clinical evaluation found no significant coronary atherosclerosis or structural cardiac disease. One patient is asymptomatic after 2 years; the second patient died suddenly at 4 months; and the third is asymptomatic but had inducible ventricular tachycardia on electrophysiologic testing 6 months after resuscitation. The mechanism of sudden death in young Southeast Asian men appears to be ventricular fibrillation. The cause of the arrhythmia is unclear, although in our patients the arrhythmia was not an isolated event; underlying predispositions to further cardiac arrest persisted.

Considerations in the long-term management of survivors of cardiac arrest.

The heterogeneity of resuscitated patients at risk of recurrent cardiac arrest serves to make their management difficult and complex. It is logical that therapy should be tailored to each patient and certainly to the mechanism whereby sudden cardiac death occurred. It is important, also, to recognize that not all resuscitated victims are at high risk for recurrence and that aggressive interventions are not necessarily mandatory. In the patient with cardiac arrest related to transient myocardial ischemia, a direct approach toward relieving ischemia seems appropriate. Antiarrhythmic agents may have a role in the treatment of some patients, but to this date the efficacy of such therapy is speculative, at best. The development and testing of agents that have "antifibrillatory" properties seems a logical approach at this time. Clearly, efforts to lessen the mortality of patients who have been resuscitated from out-of-hospital cardiac arrest are important, not only for the particular patients themselves, but also in an effort to develop rational, prophylactic interventions for the large numbers of patients with coronary heart disease who are at risk for the development of sudden cardiac death.

Reproducibility of ventricular function measurements by contrast angiography.

Interobserver reproducibility of single plane contrast angiographic measurements of end-diastolic volume (EDV/m2), end-systolic volume (ESV/m2), stroke volume (SV/m2), and ejection fraction (EF) was studied in two groups of patients. The first group (n = 42) was an unselected, consecutive series of patients in which the calculations of volume were performed manually, representing day-to-day results from a clinical quantitative angiographic laboratory. The second group (n = 31) was selected on the basis of optimal filming technique and volume calculations were performed digitally with the aid of a computer. This group characterizes the reproducibility that could be attained for investigational purposes. In the selected group, interobserver reproducibility of four regional ejection fractions was determined. The correlation coefficient (r), standard error of the estimate (Sy.x), average difference, and 95% confidence limits are given. Measurement variation accounted for 9-15% of the variance in this study for EDV/m2 (consecutive series), indicating that caution is needed when relating contrast angiographic measurements to other (e.g., noninvasive) measures of volume by simple linear regression.

Toxic and therapeutic effects of amiodarone in the treatment of cardiac arrhythmias.

Amiodarone was used to treat cardiac arrhythmias that had been refractory to conventional medical therapy. The first 70 consecutive patients treated with amiodarone in this study had at least 6 months of follow-up (range 6 to 24, mean 11) and form the basis for this report. Sixty-six patients were treated for ventricular arrhythmias and four for supraventricular tachycardias. Amiodarone therapy consisted of a loading dose of 600 mg orally twice a day for 7 days, and 600 mg daily thereafter. Doses were reduced only if side effects occurred. Because of frequent side effects, the dose was reduced from 572 +/- 283 mg per day (mean +/- standard deviation) at 45 days to 372 +/- 174 mg per day at 6 months. With a mean follow-up of 11 months in the 54 patients who continued to take amiodarone, only 4 patients had ventricular fibrillation. Three additional patients experienced recurrent sustained ventricular tachycardia in long-term follow-up. All 70 patients had extensive clinical and laboratory evaluation in follow-up. Side effects were common, occurring in 93% of patients. Thirteen patients (19%) had to discontinue the medication because of severe side effects. Fifty-six patients had gastrointestinal side effects, most commonly constipation. All patients but 1 eventually developed corneal microdeposits, and 43 patients were symptomatic. Cardiovascular side effects were uncommon. Symptomatic pulmonary side effects occurred in seven patients, with unequivocal pulmonary toxicity occurring in five. Neurologic side effects, most commonly tremor and ataxia, occurred in 52 patients. Thyroid dysfunction occurred in 3 patients, and 32 patients had cutaneous abnormalities. Miscellaneous other side effects occurred in 32 patients. Amiodarone appears to be useful in the management of refractory arrhythmias. Because virtually all patients develop side effects when given a maintenance daily dose of 600 mg, lower maintenance doses should be used. It is unknown if the more severe side effects are dose-related. Amiodarone is difficult to administer because of its narrow toxic-therapeutic range and prolonged loading phase. More importantly, the first sign of antiarrhythmic failure may be manifest as sudden cardiac death.

Prolongation of cardiac refractory times in man by clofilium phosphate, a new antiarrhythmic agent.

The electrophysiologic effects of clofilium phosphate, a new quaternary ammonium antiarrhythmic agent, were evaluated in 15 patients with a variety of cardiac dysrhythmias. Ten patients had ventricular dysrhythmias and five patients had supraventricular dysrhythmias. Clofilium was administered as a single bolus intravenously in doses ranging from 60 to 300 micrograms/kg during electrophysiologic testing. Blood pressure and heart rate were unchanged, and there were no significant side effects. Conduction time was unchanged in atrial tissue, ventricular tissue, atrioventricular node, and in the His-Purkinje system. QT intervals lengthened, atrial effective refractory period increased, and ventricular effective refractory period increased. The effective refractory period of the AV node was unchanged. Refractoriness of the bundle branches or His-Purkinje system was increased in eight patients. Inducible supraventricular arrhythmias were improved in four of four patients, and inducible ventricular arrhythmias were improved in at least five of nine patients. Clofilium is a model for an antiarrhythmic drug which should be useful in interrupting or suppressing reentrant arrhythmias because it increases refractoriness without major changes in conduction time.

Evaluation of noninvasive tests of cardiac damage in suspected cardiac contusion.

Nonpenetrating trauma to the chest can result in cardiac damage that may be overlooked because of associated injuries and the lack of obvious thoracic injury. The clinical diagnosis of important cardiac damage in this setting is difficult. We evaluated noninvasive tests for detecting myocardial damage in 100 patients with severe, nonpenetrating chest trauma. The noninvasive tests included serial ECG, serial total CPK and CPK-MB enzymes, continuous Holter monitor recording to detect dysrhythmia, and technetium-99m pyrophosphate scintigraphy. Peak CPK-MB elevations occurred in 72 patients. ECG abnormalities were noted in 70 patients, and 27 patients had Lown grade 3 or greater dysrhythmias. Fifteen patients died and all had autopsies. The noninvasive abnormalities were nonspecific and did not reflect myocardial contusion that led to clinically important cardiac complications.

Thallium-201 myocardial imaging: a comparison of the redistribution and rest images.

Forty-one patients with chest pain and suspected coronary artery disease underwent thallium-201 myocardial imaging, performed immediately following maximal treadmill exercise, also at "redistribution" 4--5 hr after exercise, and at rest 1 wk later. All had coronary angiography. All images in seven patients without coronary artery disease were normal. Twenty-seven of the 34 (79%) patients with coronary artery disease had new, exercise-induced image defects. The redistribution and rest images were identical in 15/27 (56%) patients (complete redistribution). In 10/27 (37%) patients with exercise-induced defects, some redistribution occurred but defect size on the redistribution image was larger than that on the rest images (incomplete redistribution). In 2/27 (7%) of patients with exercise-induced defects, redistribution was absent. The presence of prior myocardial infarction, regional abnormalities of left-ventricular contraction or the severity of coronary stenoses did not correlate with the presence or absence of redistribution. Overall image quality between the two studies was similar, although image collection times for the redistribution study were prolonged. We conclude that some redistribution (complete or incomplete) occurs in most patients with exercise-induced image defects. When both fixed and reversible perfusion defects are present, defect size was often larger in the redistribution image and may thus overestimate the extent of prior myocardial infarction.

Myocardial imaging with 201thallium: an analysis of clinical usefulness based on Bayes' theorem.

Rest-exercise thallium-201 (201Tl) myocardial imaging and rest-exercise electrocardiography were performed in 137 patients with suspected coronary artery disease (CAD). The final diagnosis of coronary disease was made by arteriography. Sensitivity and specificity for the ECG and thallium studies alone or combined were then determined. Based on these data, the posttest probability of CAD with a normal or abnormal test was calculated using Bayes' theorem for disease prevalences ranging from 1%--99%. The difference between the probability of disease with a normal test and the probability of disease with an abnormal test was also calculated for each prevalence range. The results demonstrate that 201Tl imaging discriminates between disease absence or presence better than does the ECG. However, both the ECG and thallium studies provide rather poor discrimination between disease and no disease when the disease prevalence is low (less than 0.20) or high (greater than 0.70). Because of this characteristic, it is unlikely that screening tests for CAD will prove useful unless the disease prevalence in the group under study is in the moderate (0.20--0.70) range.