Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer.

The cardiotoxicity of epirubicin (EPI) was evaluated clinically, radiologically, with ECG, and with multiple ECG-gated radionuclide determination of the left ventricular ejection fraction (LVEF) during rest in 135 patients with advanced breast cancer. The EPI doses were 60 mg/m2 on days 1 and 8 every 4 weeks or 45 mg/m2 plus vindesine 3 mg/m2 on the same schedule. The median cumulative dose of EPI was 500 mg/m2 (range, 47 to 1,563). Eight of the 135 patients developed congestive heart failure (CHF). Of 67 patients treated with EPI less than 500 mg/m2, none developed CHF. Among 48 patients treated with doses between 500 and 1,000 mg/m2, one had CHF (2%; 95% confidence limits, 0.1 to 11.1). Among 20 patients who received EPI from 1,000 to 1,563 mg/m2, seven developed CHF (35%; 95% confidence limits, 15.4 to 59.2). Four patients died due to cardiotoxicity. The risk of EPI cardiotoxicity at the present schedule is considerable at doses above 1,000 mg/m2. At doses between 500 and 1,000 mg/m2 the risk of CHF decreases, and at doses below 500 mg/m2, it is negligible. For all patients, the prevalence of CHF was 6% and the sensitivity of LVEF high (95%), mainly due to the low incidence of CHF. Among the 20 patients who received EPI at more than 1,000 mg/m2, the prevalence of CHF was 35% and the sensitivity only 64%. The specificity was maximally 62%. Our results suggest that LVEF is of no value as a predictor for CHF.

Combined first pass and equilibrium radionuclide cardiographic determination of stroke volume for quantitation of valvular regurgitation.

A new noninvasive procedure for quantitation of cardiac valve regurgitation was evaluated using a combination of first pass and gated equilibrium radionuclide cardiography in 38 subjects with and without cardiac valve disease. Left-sided cardiac catheterization was performed to determine the severity of mitral incompetence and aortic regurgitation semiquantitatively. In healthy subjects and in patients without valve disease, stroke volumes were nearly identical with the two methods and the correlation was high (r = 0.98 [p less than 0.001]). The mean regurgitation fraction was 13% in patients with mild mitral incompetence and 2+ aortic regurgitation, 37% in patients with moderate mitral incompetence and 3+ aortic regurgitation and 57% in patients with severe mitral incompetence and 4+ aortic regurgitation. These findings suggest that combined first pass and gated equilibrium radionuclide cardiography, being insensitive to intracardiac shunts and right-sided valve disorders, constitutes a valid noninvasive technique for quantitation of left-sided cardiac valve regurgitation.

Central hemodynamic changes after ingestion of a meal in patients with coronary artery disease.

Thirty-six patients with coronary artery disease participated in a controlled trial of the influence of food intake on central hemodynamic parameters determined noninvasively by radionuclide cardiography. Stroke volume increased considerably (23%) and heart rate was slightly higher (8%) half an hour after the meal, whereas the elevated cardiac output two hours postprandially could be ascribed entirely to relative tachycardia. No significant hemodynamic changes occurred in the patients who fasted. That the left ventricular ejection fraction was increased postprandially (3% to 4%) indicated that food intake had positive inotropic as well as chronotropic effects on the ischemic heart, even in heart failure. Afterload reduction and increased sympathetic nervous activity contribute to the changes, but the primary mechanism may be a change in resistance and blood flow in the intestinal vascular bed involved in digestion.

First-pass radionuclide determination of cardiac output: an improved gamma camera method.

A technique for noninvasive determination of cardiac output by aid of first-pass radionuclide cardiography is described. After intravenous injection of 10-15 mCi technetium-99m-(99mTc) labeled red blood cells the method requires acquisition of a first passage time-activity curve recorded with a gamma camera over the left ventricle, the background corrected left ventricular count rate recorded after complete mixing of the tracer in the circulation, and determination of the distribution volume of the tracer. The method was applied in 14 patients with heart disease of various origins and evaluated against the conventional tracer dilution technique with arterial sampling of blood activity. Cardiac output determinations by external counting ranged from 2.30 to 8.56 l/min, mean +/- s.d. 4.50 +/- 1.66 l/min and by arterial blood sampling from 1.88 to 8.96 l/min, mean +/- s.d. 4.52 +/- 1.71 l/min. An excellent correlation was demonstrated between the two techniques, r = 0.978 (p less than 0.001). When no background subtraction was applied to the left ventricular counts at equilibrium, radionuclide cardiac output values were approximately 40% higher than those obtained by arterial sampling. The new first-pass radionuclide cardiographic technique may prove a useful tool in the noninvasive evaluation of cardiac function, especially in patients with arrhythmias and/or valvular incompetence.

Antiepileptic drugs: metabolism in pregnancy.

In an open prospective clinical study, plasma clearance of phenytoin, phenobarbitone and carbamazepine was assessed in 14 epileptic patients during and after pregnancy. Plasma clearance showed a marked increase during pregnancy, reached a maximum just before or after delivery, and then decreased to early pregnancy values. The relative plasma concentration of carbamazepine-10,11-epoxide to that of carbamazepine increased similarly during pregnancy. The protein binding of carbamazepine and the epoxide was not influenced by pregnancy. A higher rate of hepatic drug metabolism, due to alteration of the physiological state in pregnancy is suggested as the most reasonable explanation. No change in seizure frequency was seen, probably because of frequent dose adjustments in order to keep plasma levels within the optimum range.

Hemodynamic effects of alcohol at rest and during upright exercise in coronary artery disease.

The hemodynamic effects of acute alcohol intoxication were studied at rest and during upright exercise in 28 patients with coronary artery disease by right-sided heart catheterization and radionuclide cardiography. The mean arterial blood pressure at rest was reduced by 5% and the left ventricular ejection fraction at rest decreased 2% because of end-systolic dilation during intoxication (serum ethanol 21 mmol/liter). No changes were observed in heart rate, stroke volume, pulmonary artery pressure, pulmonary artery wedge pressure or total peripheral resistance. No significant changes occurred in plasma catecholamines, and no changes occurred in any variable during mild exercise corresponding to a 30 to 40% heart rate increase. Thus, alcohol ingested in moderate doses causes slight impairment of left ventricular emptying and a reduction in the arterial blood pressure at rest in patients with coronary artery disease. A mild exercise load can be tolerated during alcohol intoxication without hemodynamic changes.

Cardiac performance in patients with asymptomatic alcoholic cirrhosis of the liver.

Twenty patients with biopsy-proved alcoholic cirrhosis of the liver and no cardiac symptoms entered a noninvasive investigation program in which cardiac performance was evaluated. One patient was excluded from the study because of a significant ethanol content in the serum at the time of investigation and 4 patients were excluded because of significant electrocardiographic ST-segment changes during exercise testing. Fifteen patients (12 men, 3 women, median age 47 years) who had abstained from alcohol drinking for at least 2 months were studied by exercise testing, echocardiography, measurement of systolic time intervals and left ventricular (LV) radionuclide ejection fraction (EF) at rest and during submaximal exercise. Twelve healthy persons of the same age served as control subjects. Heart rate at rest was significantly elevated in the patient group, median 90 beats/min (range 62 to 128) vs 73 beats/min (range 61 to 89) (p less than 0.02). No significant differences were found in physical work capacity and systolic time intervals, and echocardiographic parameters did not differ with the exception of left atrial dimension (median 36 mm [range 22 to 47] in the patient group and 31 mm [range 17 to 38] in the control subjects, p less than 0.05). No significant difference was found in LVEF at rest. During exercise, however, the median LVEF increased only 6% in the patients versus 14% in the control subjects (p less than 0.05). The results of this study suggest that patients with alcoholic liver cirrhosis, although free of cardiac symptoms, may have a latent or preclinical cardiomyopathy that is manifest during physical stress.

Reproducibility in the analysis of multigated radionuclide studies of left ventricular ejection fraction.

The authors determined the reproducibility (the standard deviation [SD]) in the analysis of multigated radionuclide studies of left ventricular ejection fraction (LVEF). Radionuclide studies from a consecutive series of 38 patients suspected of ischemic heart disease were analyzed independently by four nuclear medicine physiologists and four laboratory technicians. Each study was analyzed three times by each of the observers. Based on the analyses of the eight observers, the SD could be estimated by the use of a variance component model for LVEF determinations calculated as the average of the analyses of an arbitrary number of observers making an arbitrary number of analyses. This study presents the SDs for LVEF determinations based on the analyses of one to five observers making one to five analyses each. The SD of a LVEF determination decreased from 3.96% to 2.98% when an observer increased his number of analyses from one to five. A more pronounced decrease in the SD from 3.96% to 1.77% was obtained when the LVEF determinations were based on the average of a single analysis made by one to five observers. However, when dealing with the difference between LVEF determinations from two studies, the highest reproducibility was obtained if the LVEF determinations at both studies were based on the analyses made by the same observer. No significant difference was found in the reproducibility of analyses made by nuclear medicine physicians and laboratory technicians. Our study revealed that to increase the reproducibility of LVEF determinations, special efforts should be made to standardize the outlining of the end-systolic region interest.

Autonomic nervous control of postprandial hemodynamic changes at rest and upright exercise.

Postprandial hemodynamic changes were studied in healthy subjects at rest and during exercise in the upright position with and without autonomic blockade of the heart. At rest cardiac output increased 61% mostly because of a stroke volume increase accomplished by left ventricular end-diastolic dilation. These changes seemed to be dependent on the autonomic nervous system, whereas the postprandial heart rate increase did not. During exercise cardiac output was 23% higher after food intake due to a rise in both stroke volume and heart rate. These changes were apparently under influence of the autonomic nervous system, whereas left ventricular dilation was not. The present findings indicate that most of the postprandial changes in the central circulation are under control of the autonomic nervous system.

Heparin with and without dihydroergotamine in prevention of thromboembolic complications of major abdominal surgery. A randomized trial.

We compared the results of dihydroergotamine mesylate administered with low-dose heparin sodium with those of low-dose heparin given alone in a randomized trial based on 181 patients who underwent major abdominal surgery. We found no significant difference in the incidence of thromboembolism between the two groups but a higher incidence of abnormal fibrinogen uptake test results in patients given heparin alone. There was no difference in hemoglobin levels and the number of blood transfusions. We concluded that there is little, if any, clinical advantage in adding dihydroergotamine to low-dose heparin to prevent thromboembolic complications in patients who have undergone major abdominal surgery.

Prospective evaluation of chronic cardiotoxicity due to high-dose epirubicin or combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil.

In a prospective study the left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF), systolic blood pressure, ECG, and heart rate were recorded at rest and during submaximal work to compare the cardiotoxic effect of epirubicin with a combination chemotherapy without known cardiotoxicity. A total of 14 females with advanced breast cancer were treated with epirubicin at a median cumulative dose of 827 mg/m2 (range, 550-1244). These patients had previously received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or cyclophosphamide alone as adjuvant treatment, or CMF for advanced disease. The control group consisted of 11 females with advanced breast cancer given CMF only. The systolic blood pressure at rest as well as during submaximal work was significantly lower (P less than 0.05) after treatment in the epirubicin group than in the CMF controls. With regard to LVEF, the median value of 54% at rest was significantly lower after treatment in the epirubicin group than in the controls (59%). There was a significant fall in LVEF at rest and during exercise in the epirubicin group, whereas no such changes were found in the CMF controls after treatment. The RVEF was unaffected. In the epirubicin-treated group one patient developed fatal congestive heart failure, and in the remaining 13 patients treatment was discontinued due to progression of the cancer and not to cardiotoxicity. Thus, the cardiotoxicity of epirubicin changed the clinical outcome in only 1 of 14 patients with advanced breast cancer.

First passage radionuclide cardiography for determination of cardiac output: evaluation of an improved method.

A noninvasive method for determination of cardiac output by aid of first passage radionuclide cardiography is presented. As opposed to most other scintigraphic methods, a forward blood flow is measured, even in patients with valvar incompetence. In addition, the technique allows measurement of cardiac output in the presence of cardiac arrhythmias. No geometrical assumptions, corrections for radiation attenuation, loss of tracer, or empirical correction factors due to extracardiac radioactivity are required. We have evaluated the method in 19 patients with various heart diseases by comparison of the radionuclide cardiac outputs with those derived from the thermodilution technique performed simultaneously. Eight patients had valvar incompetence and 2 had cardiac arrhythmias. The mean radionuclide and thermodilution cardiac output values were 5.03 l/min (SD 1.21) and 5.18 l/min (SD 1.09), respectively. The 95% confidence interval for the bias was -0.40 to 0.10 l/min, and correlation analysis demonstrated an excellent correlation between results obtained with the two methods, r = 0.91 (P less than 0.001). This study shows that the improved gamma camera method represents a valid noninvasive technique for determination of cardiac output.

The value of the left ventricular ejection fraction in the treatment of angina pectoris following acute myocardial infarction: a randomized double blind study.

Radionuclide determination of left ventricular ejection fraction was performed at hospital discharge and one month later in 60 patients who had suffered acute myocardial infarction. At the first determination, the patients were randomized into two groups. In the first group, the cardiologist who cared for the patients was provided with the result of the determination of the ejection fraction whereas, in the second group, the result was withheld. At a 'blinded' evaluation two months after hospital discharge, 7 of those patients (24%) from the group where the cardiologist knew the ejection fraction and 11 of the patients (38%) in whom this result was withheld complained of angina pectoris on exertion (ns). The medication of the patients did not differ in the two groups. No significant difference was found in the values of the ejection fraction in patients with and without angina pectoris. In this controlled study, we were not able to document a clinical effect by routinely determinating left ventricular ejection fraction in patients with acute myocardial infarction in the treatment of angina pectoris.

Right ventricular ejection fraction determined in three projections.

The right ventricular ejection fraction (RVEF) was successively determined in three projections in ten healthy volunteers aged 28-53, mean 37 years, with a first-pass technique using 99Tcm-labelled red blood cells and a gamma camera coupled to a computer. In the anterior-posterior projection (AP) the mean RVEF was 39.3%, range 26-49%, in the left anterior oblique (LAO) 43.7% (36-58), and in the right anterior oblique (RAO) 44.5% (36-54). These mean values do not differ significantly (P = 10%). The results from one of the subjects were withdrawn, as they deviated markedly from the general pattern, and the data were reanalysed from the remaining 9 subjects. Now the mean RVEF in the AP projection was 38.2%, which is significantly lower (P = 1%) than the corresponding RVEF of 44.3% in the LAO projection and of 45.2% in the RAO projection. Our results suggest that when using the classic first-pass technique, the right ventricle histograms will in any projection be influenced by the activity in the right atrium and the large vessels.

Evaluation of radiocardiographic methods for determination of cardiac output and right and left ventricular ejection fractions using a cardiac phantom.

Cardiac output and ejection fractions of the cardiac ventricles are valuable measures of cardiac function. Noninvasive radionuclide techniques for determination of these measures are based on analysis of different data: first passage low frequency, first passage high frequency and multigated equilibrium data. We have evaluated the principles of these methods using a dynamic cardiac phantom. Radiocardiographic determinations of cardiac output and right and left ventricular ejection fractions showed excellent correlation against true phantom values: r = 0.993 (p less than 0.001), r = 0.978 (p less than 0.01) and r = 0.943 (p less than 0.05), respectively. Thus, the findings of the present study demonstrate a high validity of current radiocardiographic measures of cardiac function.

A comparison of dipyridamole thallium 201 scintigraphy and clinical examination in the determination of cardiac risk before arterial reconstruction.

Preoperative clinical examination, including a 12-lead resting ECG, and planar dipyridamole thallium imaging (DTI) were compared in a prospective study of 65 vascular surgical patients in regard to their value for predicting postoperative cardiac complications. Fifty-three patients underwent abdominal vascular procedures and 12 were operated on for peripheral artery disease. Thirty-six patients had ischemic heart disease (IHD) and/or abnormal findings from 12-lead resting ECG. Of these 36 patients, 11 had nonfatal cardiac complications. The remaining 29 patients were free of IHD and had normal results from ECG. No complications occurred among these 29 patients. There was no postoperative death. Thallium imaging results were abnormal in 45 patients, showing either redistribution and/or scar tissue or low washout. In 18 of these patients major changes with redistribution were present in all projections. Among these patients, 9 had a nonfatal cardiac complication. In the 27 patients with abnormalities in only one or two projections, only 2 had a cardiac event postoperatively. No cardiac complications occurred in patients with normal thallium scintigraphy findings. The patients were operated on irrespective of the results of the scans, and all recovered from any cardiac complications that occurred. In vascular surgical patients with previous IHD and/or abnormal findings from resting ECGs further risk stratification is achieved with DTI.

[Observer variations in computerized 201 thallium myocardial scintigraphy]. / Observatørvariationen ved kvantitativ 201Thallium-myokardieskintigrafi.

The observer variation (reproducibility) in computerized 201Tl scintigraphy was determined by describing the results of 20 investigations as being normal, suggestive of ischaemia or representing scar tissue. At an interval of two months, two physicians evaluated the results independently. As to normality, the interobserver variation was small, the level of agreement corrected for chance agreement, the kappa coefficient, being from 69-100%. For the diagnosis of ischaemia, kappa was also high, 58-100%. The intraobserver variations were of the same magnitude. In scar tissue, the kappa coefficients were somewhat lower. The present method has an acceptable observer variation in distinguishing between a diseased and a normal myocardium. The lower kappa coefficients for scar tissue and recent findings showing that persistent defects on the delayed images are viable tissue in 30% of the cases, makes it difficult to diagnose scar tissue.

[201-thallium myocardial scintigraphy before and after percutaneous transluminal coronary angioplasty]. / 201thallium myokardieskintigrafi før og efter perkutan transluminal koronar angioplastik.

We describe our experience from the first 30 patients treated with percutaneous transluminal coronary angioplasty (PTCA) in the Cardiologic Department P, Gentofte Hospital. The main purpose was to evaluate the value of thallium scintigraphy performed before and three months after PTCA. After PTCA, 23 (77%) had no angina and 22 (73%) had normal exercise-ECG. On the basis of the scintigraphies before PTCA, the patients were divided into two groups: In group 1, five had normal scintigraphy and 14 reversible perfusion defects only. In group 2, all 11 patients had both persistent and reversible defects. In patients without persistent defects, significantly more were free from angina. No difference was observed between group 1 and 2 in percentage stenosis of the vessel or in reduction of the diameter. Significant reduction in the extent of reversible perfusion defects after PTCA was observed in both groups and also in the extent of persistent defects in group 2. In about 1/3 of the patients, the changes in percentage stenosis after PTCA and in the perfusion as judged by the scintigraphies differed. Therefore, as the two methods supplement each other, the main conclusions are: 1) Evaluation of the revascularization procedure is more reliable if a scintigraphy is obtained both before and after PTCA than if only coronary arteriography is performed. 2) Scintigraphy alone suffices for the three-month follow-up examination, partly because it gives better information about the myocardial perfusion than does the arteriography, partly because scintigraphy is a noninvasive procedure.

[Cimetidine and creatinine clearance]. / Cimetidin og kreatininclearance.

Cimetidine lowers secretion of creatinine in the renal tubuli in healthy individuals and persons with chronic renal disease. The conditions in patients with renal transplants have hitherto been unknown. The renal clearance of endogenic creatinine (CKrea) was investigated prior to and after an intravenous bolus injektion of cimetidine (5 mg/kg) in nine patients with renal transplants. The rate of glomerular filtration (GFR) was determined by clearance investigation of 125I-thalamate (CTh). CKrea fell 29% from 65 ml/min (median) to 46 ml/min (p less than 0.01), whereas GFR remained unchanged. The fractionated creatinine clearance (CKrea/CTh) fell therefore from 1.43 (median) to 1.03 (p less than 0.01). It is concluded that cimetidine reduces creatinine secretion in patients with renal transplants and this should be borne in mind when the function of the graft is assessed solely with CKrea.

The utility of EMG interference pattern analysis in botulinum toxin treatment of torticollis: a randomised, controlled and blinded study.

OBJECTIVE: The significance of electromyography (EMG) guidance in botulinum toxin (BT) treatment has been much debated. The aim of this study was to evaluate if EMG guidance in the treatment of torticollis in BT-naive patients had a better outcome than treatment after clinical evaluation alone. METHODS: Twenty-six patients with torticollis were included and treated for 1 year in this prospective, blinded study. Quantitative EMG was performed simultaneously in the four most frequently affected muscles: the sternocleidomastoid muscles and the posterior neck muscles on both sides. EMGs were analysed for turns per second. Clinical ratings were performed by an experienced neurologist (A). Injections were given by another neurologist (B), who was blinded to the ratings. In group 1, the results of the EMG were available to the treating neurologist B, whereas in group 2, neurologist B was blinded. In group 1, treatment with BT was given when turns per second were higher than 100. RESULTS: In patients treated guided by EMG, clinical outcome, evaluated by objective ratings, was better than in patients treated based on clinical judgement alone (p = 0.05). In group 2, 105 muscles were treated with BT. Of these, 37 did not show dystonic EMG activity. CONCLUSIONS: Treatment with BT guided by EMG results in better clinical outcome than treatment without EMG and reduces the amount of BT used. SIGNIFICANCE: EMG guidance by interference pattern analysis may optimise BT treatment in torticollis by a more precise injection and may reduce side effects and the risk of development of antibodies to BT.