The cardiac arrhythmia suppression trial.
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Biomedical subjects
Publications and source records attributed to D L Heene.
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Six months after a pneumonectomy for myeloma, which had preoperatively been indistinguishable from bronchial carcinoma, a 50-year-old man presented with shortage of breath, cyanosis and episodes of syncope on standing or walking, symptoms which improved on lying down (platypnea). On one occasion these symptoms necessitated controlled artificial ventilation, but even at an inspiratory oxygen saturation of 100%, blood gases only partially improved (pCO2 27 mm Hg, pO2 67 mm Hg, O2 saturation 93%). Right heart catheterization in recumbency revealed a right to left shunt at atrial level of 37% of systemic flow. Contrast medium injection into the inferior vena cava near the heart demonstrated cardiac displacement and rotation. Part of the inferior vena cava flow passed into the left atrium via a patent foramen ovale: it is likely that this shunt increased in the upright position. After surgical closure of the patent foramen ovale and partial relocation of the heart (with a vicryl net) the patient has now remained free of symptoms for 5 years.
The Heparin Study in Internal Medicine (HESIM) compares the efficacy and safety of an unfractionated (UF) heparin with a low molecular weight (LMW) heparin (CY 216 D) for prevention of proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) in medical inpatients with a high risk for development of thromboembolism. Patients are randomized and receive three times daily 5000 IU UF heparin or once daily 3100 IU LMW heparin and two placebo injections subcutaneously for 10 days. All patients are screened for the presence of proximal DVT at day 1 and 10 by real-time B-mode compression sonography and for PE by repeated clinical examinations. Perfusion scintigraphy is used for confirmation of the clinical diagnosis of PE. The study protocol includes a stratified randomization of patients on admission to the hospital according to one of the following main diagnoses: malignant disease, cardiovascular disease, bronchopulmonary disease, neurologic disease, and other diseases. The present study may serve as a model for further clinical trials in medical inpatients using the biometric approach of statistical analysis for proving equivalence of drug efficacy, and to adopt less sensitive but noninvasive methods for the detection of primary endpoints.
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In a prospective study we randomly allocated 50 patients with acute ischaemic stroke in the area of the middle cerebral artery within 12 hours after onset to two moderate hypervolemic haemodilution regimen consisting of 500 ml of 10% hydroxyethyl starch per day for 10 days. In the high haematocrit group the target haematocrit of 41-42% was achieved by 0-3 phlebotomies and additional replacement of that volume with the colloid in 3 days. In the low haematocrit group with 1-4 phlebotomies a target haematocrit of 37-38% was reached in 4 days. The groups did not differ regarding age, risk factors, haematocrit and neurological score. The improvement of the disturbed blood rheology was more pronounced in the low haematocrit group. One death occurred in each group. The neurological score showed a significantly greater increase in the low haematocrit group with +59% at day 5 and +125% at day 11; the data for the high haematocrit group were +34% and +89% respectively. We calculated a correlation (r = 0.36, p less than 0.02) between the rise in neurological score and the reduction of haematocrit. Our data suggest but not do prove that an early start on moderate hypervolemic haemodilution is beneficial in patients with acute ischaemic stroke and disturbed blood rheology.
Fractionated and unfractionated heparins are widely used as antithrombotic agents. Because of their heterogeneous composition, it is difficult to study the pharmacokinetics of these drugs. We now report on a new method for labeling low molecular weight heparins with 131I by binding tyramine to the anhydromannose end of the molecules. We examined the pharmacokinetics of the compound by intravenous injection of 131I-tyramine-heparin into Wistar rats. About 18% of the activity was found in the liver, whereas 33% was detected in urine. Biological activity in terms of Factor Xa inhibition was measurable. Since evidence from cell culture experiments implies that reticuloendothelial cell system receptors might be involved in heparin metabolism, maleylated BSA, a substance known to block scavenger receptors, was injected before the radiolabeled heparin compound. The liver uptake was reduced from 17.4 to 4.8%. Injection of unfractionated heparin before tracer application caused a considerable increase in urine excretion of the tracer substance. To our knowledge, this is the first report that liver uptake of heparins is linked to scavenger receptor mediated mechanisms in vivo. This interaction of heparins with scavenger receptors might play an important role in the biology of the vessel wall.
A sensitive, reproducible and rapid quantitative microtiter assay for factor XIII activity is described. The assay is based on incorporation of a soluble amine substrate into casein attached to polystyrol microtiter plates and detection of bound substrate with a monoclonal antibody-enzyme conjugate. Defibrination of plasma samples is not required. The assay shows strong correlation with the immunologic assay for factor XIII catalytic subunit a (r = 0.94), the factor XIII dansylcadaverine assay (r = 0.83), and the factor XIII clot solubility test. Normal values detected in healthy blood donors were in the range of 74% to 117%, with a mean value of 96.9% and a median value of 97.8%; pooled normal plasma was used as a reference. Since the assay is performed in a single microtiter plate and requires few reagents and short incubation periods, it can be easily adapted for clinical use.
The risk factor patterns for coronary heart disease in China, Japan and Germany were studied. 6,025 Germans, 7,580 Japanese and 2,047 Chinese aged 30-59 were investigated following the protocol of the Göttingen Risk, Incidence, and Prevalence Study carried out in West Germany in 1982. It is concluded that in China, the risk factor intervention focuses mainly on smoking and hypertension; smoking also remains the most important risk factor in Japan; while in Germany the major targets are obesity and hyperlipidemia. However, about 38% of the participants from West Germany showed 3 or more risk factors accumulated per person. Thus the multifactorial risk factor reduction might be necessary in Germany.
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In Asia coronary heart disease mortality is almost 10 fold less frequent than in European countries. These findings attract interest to search for different risk factor patterns. From 1982 to 1985 epidemiologic surveys were carried out in China (n = 2047), Japan (n = 7580) and Germany (n = 6052). Healthy, male subjects, aged 30 to 59 years were enrolled. The prevalence rate of hypertension for the Germans was 20% versus 18% for the Japanese, and 11% for the Chinese. About 69% of Chinese, 55% of Japanese, and 37% of Germans were smokers. About 66% of the Germans were overweight (BMI greater than 25), 17% of the Japanese, and 11% of the Chinese. The highest risk group with cholesterol levels of greater than 300 mg/dl included no Chinese subject, 0.1% of the Japanese, but 5% of the Germans. The lipoprotein profiles among the Japanese and the Chinese collectives typically showed antiatherosclerotic characteristics, whereas most Germans exhibited profiles which support development of atherosclerosis. About 36% of the participants from Germany showed 3 or more risk factors accumulated per person (Japan and China 5%). Multifactorial risk factor reduction for Germany is recommended.
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166 patients aged 40-80 years were included in a controlled, randomized, double-blind study to determine the efficacy and safety of a single daily injection of a low molecular weight (LMW) heparin for prevention of deep-vein thrombosis compared to low dose conventional heparin. Patients received 1 x 1.500 aPTT units of a LMW heparin fraction (plus 2 x placebo injection) or 3 x 5.000 IU of an unfractionated heparin. During 10 days of treatment, patients underwent repeated clinical investigation, serial impedance plethysmography, and Doppler sonography for detection of thrombosis of the lower limbs. Combined application of these methods revealed evidence of thrombosis in 4.5% of patients on unfractionated heparin and 3.6% of patients on LMW heparin. Subcutaneous hematomas were significantly smaller in diameter upon treatment with LMW heparin (p less than 0.001). Antithrombin III levels were significantly higher at the end of the observation period in the LMW heparin group (p less than 0.005). Thrombocyte count, transaminases, creatinine, and haemoglobin did not change in either group. The results indicate that LMW heparin administered by a single s.c. dose daily may be as effective as low dose heparin in prevention of deep venous thrombosis in medical inpatients.
A double-blind study was carried out to compare the effects of a premedication with 4 x 500 mg dimethylpolysiloxane (DPS)/24 hours and with 2 x 500 mg/12 hours before abdominal ultrasonography. The investigations covered 13 abdominal regions in specified planes. The incidence of the unobscured presentation of the selected organs and organ sections per patient served as a basis for a sonography index. This index was 67%, without significant difference between the two groups. We believe that the optimal conditions for sonography are given when the patient is fasting and two 500 mg doses of DPS are administered, one in the evening before and one in the morning at the day of investigation.
Differentiation between hypertrophic cardiomyopathy and hypertensive heart disease is a diagnostic challenge. M-mode echocardiography only permits assessment of hypertrophy in limited areas of the left ventricular wall. 2-D echocardiography allows visualization of most of the myocardium. To assess the reliability of conventional M-mode echocardiographic and 2-D echocardiographic criteria in patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HY), 30 patients with hypertrophic cardiomyopathy and 30 patients with hypertension and severe cardiac hypertrophy were examined using M-mode and 2-D echocardiography. Although the M-mode echocardiographic features showed statistically significant differences between the mean values in the two groups, the degree of overlap made the differentiation of the individual patients difficult. The diagnostic sensitivity and specificity of classic echocardiographic features were assessed: ventricular septal thickness greater than or equal to 1.5 cm, 90% and 43% (sensitivity and specificity, respectively); ventricular septal thickness to posterior wall ratio greater than or equal to 1.5, 83% and 56%; cross-sectional area at papillary level greater than 21 cm2m-2, 80% and 73%; septal segment of the myocardial ring at papillary level greater than 6.5 cm2m-2, 80% and 87%; and the combined criteria of cross-sectional area at papillary level greater than 21 cm2m-2 and septal segment greater than 6.5 cm2m-2, 77% and 93%. Quantitative 2-D echocardiography is useful to differentiate patients with hypertrophic cardiomyopathy from those with secondary myocardial hypertrophy due to hypertension. Hypertrophic cardiomyopathy is characterized by a spectrum of different morphological patterns of hypertrophy. Patients with the predominant region of hypertrophy in the anterolateral free wall or the apical region of the left ventricle were not detected with our quantitative method. Patients with this type of hypertrophy are relatively rare in the western population.
Fifty patients presenting with acute deep-vein thrombosis were randomized in a prospective, controlled study to determine the safety and efficacy of a treatment with low-molecular-weight (LMW) heparin compared with unfractionated heparin. LMW heparin (n = 24) was administered twice daily subcutaneously at a dose of 2 X 150 anti-Xa units/kg body weight, and unfractionated heparin (n = 26) was given intravenously by continuous infusion at a dose of 450 anti-Xa units/kg body weight daily for 10 days. Doses were adjusted to maintain peak anti-Xa levels between 0.5 and 1.0 anti-Xa units per milliliter. One patient in the unfractionated heparin group and 2 patients in the LMW heparin group suffered from bleeding complications. Two patients on LMW heparin and on unfractionated heparin had high evidence of pulmonary embolism based on defects on ventilation-perfusion scintigraphy. Control phlebography and duplex sonography demonstrated a significant improvement during both treatment regimens. Reperfusion of the deep-vein system was 70% with LMW heparin and 75% with unfractionated heparin. The anti-Xa levels were significantly higher in the LMW heparin group, and activated partial thromboplastin and thrombin clotting times were significantly higher in the group receiving unfractionated heparin. Thrombin-antithrombin III complexes and D-dimer concentration decreased during the treatment, but did not differ between the two regimens. At the end of the treatment period with LMW heparin, protein C and antithrombin III were significantly higher.
The phenomenon of complex formation between fibrinmonomer and fibrinogen degradation products was investigated by means of adsorption of FDP to insolubilized thrombin-modified fibrinogen (FM-ag). Since it could be demonstrated that there are different adsorption characteristics for early FDP and late FDP, the possibility of separation of FDP by means of affinity chromatography on FM-ag columns was evaluated using plasmic digests of 3H-Ac-labelled fibrinogen. The identification of FDP was performed by disc-electrophoresis. The results indicate that the adsorption of early FDP is comparable to the behaviour of fibrinogen, whereas late FDP show essential difference in the affinity towards FM-ag, evident by the result that fragment E adsorbs only to a minimal extents. Fragments D and E derived from fibrinogen as well as from non-crosslinked fibrin, revealed identical adsorption characteristics. Under specified conditions the procedure is suitable as a preparative method for the separation of fragments D and E.