Dosage dependent hormonal counter regulation to combination therapy in patients with left ventricular dysfunction.

UNLABELLED: The present study attempts to assess the efficacy combination therapy for heart failure. Genuine dose-response studies on combination therapy are not available and published studies involved adding one drug on top of 'usual treatment'. Sixteen different dosage combinations of trandolapril and bumetanide was tested in a double blind, double placebo-controlled, randomized, multiple cross-over study in a 16 times six balanced incomplete Latin square design. Patients reported optimal quality of life on the sub maximal dose bumetanide. Bumetanide decreased left ventricular function and increased heart rate and plasma noradrenaline in a dose dependent manner. Doses of bumetanide of more than 0.5 mg, given twice daily significantly decreased the quality of life and increased diuresis. Weight loss was maximal on 0.5 mg bumetanide twice daily. Trandolapril significantly reduced systolic blood pressure with the maximal effect at 0.5 mg daily. Both drugs significantly increased renin concentration with a significant potentiating interaction. It was not possible to detect beneficial effects of combination therapies. The optimal dosage of Bumetanide appeared to be 0.5 mg twice daily based on its effect on quality of life and weight loss. Estimated by the reduction in systolic blood pressure the optimal dosage of Trandolapril appeared to be 0.5 mg once daily. CONCLUSIONS: It appears that patients should be given less than the usually recommended dosages. Patients may be treated with a low dose loop diuretic, if signs of water retention are present or if symptomatic relief is desired.

[Contrast echocardiography. Basic principles and clinical applications]. / Kontrastekkokardiografi. Basale principper og kliniske applikationer.

Recent advances in ultrasound technology and intravenous contrast agents have made it possible for contrast echocardiography to move from bench to bedside. Ultrasound contrast agents enhance endocardial border delineation and the Doppler signal, which may improve the diagnostic accuracy of echocardiography in selected patients. The most exciting feature of contrast echocardiography is its capability to achieve a quantitative assessment of myocardial perfusion, and the method may thus provide a range of clinical applications in patients with ischaemic heart disease.

Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender joints, the erythrocyte sedimentation rate, and hemoglobin: longterm course and association to radiographic progression.

OBJECTIVE: To investigate the association of individual plots and time-integrated values of repeated measures of inflammatory variables with radiographic outcome in rheumatoid arthritis (RA). METHODS: In 112 patients with RA, examinations of joint swelling and joint tenderness of 68 joints, and measurement of hemoglobin (Hb) and erythrocyte sedimentation rate (ESR) were performed each year for up to 22 years after the first visit. For each of these 4 variables, the patients were divided arbitrarily into 5 characteristic subgroups by means of inspection of individual plots of longitudinal observations of the variables and divided into 5 other subgroups according to 20% percentiles of the cumulative mean values of the variables. The outcome of the subgroups was evaluated by varying degrees of radiographic events estimated by Larsen scoring of consecutive radiographs of 46 joints. RESULTS: An increasing number of radiographic events in subgroups with increasing severity (increasing values of joint swelling, joint tenderness, and ESR, decreasing values of Hb) was seen for both the arbitrary subgroups and the percentile subgroups of joint swelling, Hb, and ESR, whereas the association of joint tenderness to radiographic progression was weak. CONCLUSION: A highly significant association between inflammatory variables and radiographic outcome could be observed, indicating that the degree of inflammation is important for the development of destructive joint damage in RA.

[The effect of reduced sodium intake on blood pressure, body weight, renin, aldosterone, catecholamines, cholesterol and triglycerides. A meta-analysis]. / Effekten af reduceret saltindtagelse på blodtryk, kropsvaegt, renin, aldosteron, katekolaminer, kolesterol og triglycerid. En metaanalyse.

The purpose of the present study was to estimate the effects of reduction in sodium intake on blood pressure, hormones and lipids. Data were extracted from randomised studies and statistically integrated in a meta-analysis. In 58 trials of hypertensive persons, a reduction in sodium intake of 118 mmol reduces systolic BP by 3.9 mmHg (CI: 3.0-4.8) (p < 0.0001) and diastolic BP by 1.9 mmHg (CI: 1.3-2.5) (p < 0.0001). In 56 trials of normotensive persons, the reduction in sodium intake reduced SBP by 1.2 mmHg (CI: 0.6-1.8) (p < 0.0001) and DBP by 0.26 mm Hg (CI: -0.3-0.9) (p = 0.12). Plasma renin and alsterone increased by a factor of three to four (p < 0.0001). There was a significant decrease in body weight and an increase in noradrenaline, cholesterol and LDL cholesterol. In conclusion the present results do not warrant a general recommendation of reducing sodium intake.

Effects of sodium restriction on blood pressure, renin, aldosterone, catecholamines, cholesterols, and triglyceride: a meta-analysis.

CONTEXT: One of the controversies in preventive medicine is whether a general reduction in sodium intake can decrease the blood pressure of a population and thereby reduce the number of strokes and myocardial infarctions. In recent years the debate has been extended by studies indicating that reduced sodium intake has adverse effects. OBJECTIVE: To estimate the effects of reduced sodium intake on systolic and diastolic blood pressure (SBP and DBP), body weight, and plasma or serum levels of renin, aldosterone, catecholamines, cholesterols, and triglyceride, and to evaluate the stability of the blood pressure effect in relation to additional trials. DATA SOURCES: MEDLINE search from 1966 through December 1997 and reference lists of relevant articles. STUDY SELECTION: Studies randomizing persons to high-sodium and low-sodium diets were included if they evaluated at least one of the effect parameters. DATA EXTRACTION: Two authors independently recorded data. DATA SYNTHESIS: In 58 trials of hypertensive persons, the effect of reduced sodium intake as measured by urinary sodium excretion (mean, 118 mmol/24 h) on SBP was 3.9 mm Hg (95% confidence interval [CI], 3.0-4.8 mm Hg) (P<.001) and on DBP was 1.9 mm Hg (95% CI, 1.3-2.5 mm Hg) (P<.001). In 56 trials of normotensive persons, the effect of reduced sodium intake (mean, 160 mmol/24 h) on SBP was 1.2 mm Hg (95% CI, 0.6-1.8 mm Hg) (P<.001) and on DBP was 0.26 mm Hg (95% CI, -0.3-0.9 mm Hg) (P=.12). The cumulative analysis showed that this effect size has been stable since 1985. In plasma, the renin level increased 3.6-fold (P<.001), and the aldosterone level increased 3.2-fold (P<.001); the increases were proportional to the degree of sodium reduction for both renin (r=0.66; P<.001) and aldosterone (r=0.64; P<.001). Body weight decreased significantly, and noradrenaline, cholesterol, and low-density lipoprotein cholesterol levels increased. There was no effect on adrenaline, triglyceride, and high-density lipoprotein cholesterol. CONCLUSION: These results do not support a general recommendation to reduce sodium intake. Reduced sodium intake may be used as a supplementary treatment in hypertension. Further long-term studies of the effects of high reduction of sodium intake on blood pressure and metabolic variables may clarify the disagreements as to the role of reduced sodium intake, but ideally trials with hard end points such as morbidity and survival should end the controversy.

Distribution of liver haemosiderin iron in 187 patients with various types of hepatic diseases.

The purpose of this study was to evaluate the distribution of haemosiderin iron in various regions of the liver (central, intermediary and peripheral hepatocytes, Kupffer cells, portal macrophages and bile duct epithelial cells) in 174 patients with different hepatic diseases (alcoholic cirrhosis (n = 49), alcoholic steatosis (n = 60), non-alcoholic cirrhosis (n = 16), acute hepatitis (n = 20), clinically overt untreated hereditary haemochromatosis (n = 3), miscellaneous disorders (n = 26)), and in 13 subjects with a normal liver biopsy. Furthermore, the relationship between liver haemosiderin iron, biochemical iron status markers and biochemical liver tests was investigated. In haemochromatosis iron was consistently present in all examined regions of the liver, and in 43% of patients with alcoholic liver disease haemosiderin was present in at least one region of the liver lobule. In 65% of patients with acute hepatitis, haemosiderin was present in macrophages and Kupffer cells. In other hepatic diseases and in normal livers, haemosiderin was rarely seen. Regression analyses showed a correlation between iron status markers in most patients, except in those with high serum aspartate aminotransferase levels. In conclusion, haemosiderin iron is distributed in a typical pattern in haemochromatosis, alcoholic liver disease and acute hepatitis. Both histochemical liver iron and serum ferritin are of value as indirect markers of liver iron stores in patients with moderate hepatocellular damage.

No effect of the calcium antagonist, isradipine, on plasma catecholamines in irreversible chronic obstructive pulmonary disease (COPD). A randomized, double-blind, placebo-controlled study.

Calcium antagonists have been claimed to decrease the pulmonary artery pressure and increase oxygen uptake and cardiac output in patients with chronic obstructive pulmonary disease (COPD). This should tend to decrease the plasma levels of catecholamines. The purpose of the present study was to assess the effects of the vasodilating calcium antagonist, isradipine, on resting and exercise levels of catecholamines in patients with COPD. Eighteen patients with severe respiratory insufficiency (FEV1<1.01) were investigated. During maximum exercise, the baseline levels of plasma noradrenaline rose from 2.27 nmol/l (0.41-7.66: mean, range) to 3.86 nmol/l (1.3-12.2) (P = 0.0002) and plasma adrenaline rose from 0.39 nmol/l (0.07-1.02) to 0.64 nmol/l (0.07-1.77) (P = 0.0001). The patients were randomly allocated to receive either capsules of placebo or capsules of 5 mg of isradipine and were reinvestigated after 2 h and 3 months. There was no significant difference between the two groups concerning the change in plasma catecholamines, neither at rest nor at exhaustion. Furthermore, the increase in catecholamines during exercise in the two groups did not differ from each other, neither before administration of isradipine nor after. In conclusion, a vasodilating calcium antagonist did not alter the resting level or exercise induced increase in plasma catecholamines.

Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety.

A number of randomised studies indicate that a single high dose of aminoglycoside every 24 h may be more efficient and less toxic than the same dose divided into multiple daily doses. In the meta-analysis of 16 studies described here, which included more than 1200 patients, the relative chance (i.e. the relative risk, RR) of cure of the single-dose regime compared with the multiple-dose regime was 1.027, indicating that the single daily dose regime had a 2.7% higher cure rate (NS). The RR of avoiding nephrotoxicity was 1.001 (NS) and the RR of avoiding ototoxicity was 1.001 (NS). It is concluded that there is no difference concerning efficacy and safety between single-dose and multiple-dose regimes for administration of aminoglycosides.

[Magnesium treatment of patients with acute myocardial infarction. A meta-analysis]. / Magnesiumbehandling af patienter med akut myokardieinfarkt. En metaanalyse.

The object of the study was to investigate the effect of intravenous magnesium in acute myocardial infarction. It was carried out as an overview of available randomized trials in which patients were allocated to receive either magnesium or placebo, the trials having taken place in the coronary care units of several hospitals. The subjects were 2438 patients with acute myocardial infarction in nine blind randomized trials combined in a meta-analysis and 54,822 patients in one unblinded randomized multi-centre trial. The main outcome measure was the relative chance of survival and relative chance of avoiding ventricular tachyarrhythmia. In the meta-analysis, the relative chance of survival was significantly increased in the magnesium group (RR = 1.049, 95% CI = 1.020-1.078, p < 0.0007). Hypothetically 25 papers with a mean of 271 patients and an RR of 1.0 should be included to make the result insignificant. The relative chance of avoiding ventricular tachyarrhythmia was not significantly increased in the magnesium group (RR = 1.041, 95% CI = 0.996-1.089, p = 0.07). The risk of accepting the null hypothesis (RR = 1.0) if the alternative hypothesis (RR = 1.041) is correct is 0,58 (the type 2 error). There was no effect on survival in the multi-centre study (RR = 0.996). It is concluded that intravenous treatment with magnesium increases survival in patients with acute myocardial infarction by 4.9% in nine blind trials, but has no effect in a large open multi-centre study.

[No grounds for vasodilatory treatment in pulmonary hypertension]. / Intet grundlag for behandling af pulmonal hypertension med vasodilatation.

Large scale review of the literature on vasodilatory treatment of secondary pulmonary hypertension reveals an abundance of non-controlled and non-blinded studies. There is only a handful of randomized, placebo-controlled trials. These few studies cannot support the findings from non-controlled studies showing beneficial haemodynamic effects. Only two controlled studies showed clinically relevant parameters such as working capacity, mortality and morbidity, and vasodilators do not seem to possess beneficial influence on these parameters. It is concluded, that until now no publication has been able to convincingly demonstrate any long-term clinically beneficial effects of vasodilators in patients with secondary pulmonary hypertension.

Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis.

L-Thyroxine (L-T4) in the treatment of thyroid disease resulting in reduced serum thyrotropin (TSH) has been associated with reduced bone mass and thus the potential risk of premature development of osteoporosis. However, several recent studies have failed to show such a detrimental effect. These disagreements are probably due to only a small number of patients taking part in each study, decreasing the change of finding significant differences and increasing the risk of missing a real difference (type 1 and 2 errors, respectively). We therefore performed a meta-analysis on the available papers (N = 13), in which bone mass was measured in the distal forearm, femoral neck or lumbar spine in a cross-sectional manner in women with suppressed serum TSH due to L-T4 treatment and in a control group. The women were divided according to their pre- and postmenopausal state, because preserved estrogen production plays a protective role against irreversible bone loss. Based on the number of measurements performed on the different sites of the skeleton, a theoretical bone composed of 30.4% distal forearm, 28.8% femoral neck and 40.8% lumbar spine could be constructed in premenopausal women (441 measurements). A premenopausal woman at an average age of 39.6 years and treated with 164 micrograms L-T4/day for 8.5 years, leading to suppressed serum TSH, had 2.67% less bone mass than controls (NS), corresponding to an excess annual bone loss of 0.31% after 8.5 years of treatment (NS). The risk of not detecting an excess bone loss of at least 1% per year (type 2 error) was p < 0.15.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac performance and thyroid function. The correlation between systolic time intervals, heart rate and thyroid hormone levels.

UNLABELLED: In the search for a clinical correlate to thyroid function, correlations were sought between the plasma level of thyroid hormones and the cardiac function, assessed by heart rate and the systolic time intervals. The present study is the first to 1) use a curvilinear correlation and 2) do so in the entire hormone range. A third degree Chebychew's regression equation was used to enable curvilinear correlation. In a population of 10 hypothyroid, 14 euthyroid, and 25 hyperthyroid patients a statistically significant curvilinear correlation was found between the thyroid hormone levels and the systolic time intervals. The correlation coefficients showed the heart rate equally correlated to the thyroid hormone levels as the best correlated of the systolic time intervals. The correlation between the heart rate and T3 was almost linear, with a heart rate increase of 4 beats/minute with each increase in plasma T3 of 1 nmol/l. CONCLUSION: The thyroid function reflects in the cardiac function in a curvilinear regression between T3 and systolic time intervals and in an almost linear regression between T3 and heart rate. The variation, however, is too great and the slope too low, to suggest the use of the heart rate as a clinical correlate to thyroid function.

Influence of oral magnesium supplementation on cardiac events among survivors of an acute myocardial infarction.

OBJECTIVE: To investigate the effect of long term oral magnesium treatment on incidence of cardiac events among survivors of an acute myocardial infarction. DESIGN: Double blind, placebo controlled parallel study in which patients were randomised to treatment or placebo. SETTING: Two coronary care units and corresponding outpatient clinics. SUBJECTS: 468 survivors of an acute myocardial infarction (289 men and 178 women) aged 31-92. INTERVENTIONS: One tablet of 15 mmol magnesium hydroxide or placebo daily for one year. MAIN OUTCOME MEASURES: Incidences of reinfarction, sudden death, and coronary artery bypass grafting in one year. RESULTS: There was no significant difference between treatment and placebo groups in the incidence of each of the three cardiac events, but when the events were combined and drop outs were excluded from calculations there was a significantly higher incidence of events in the treatment group (56/167 v 33/153; relative risk 1.55 (95% confidence interval 1.07 to 2.25); p = 0.02). When the timing of events was incorporated by means of a Kaplan-Meier plot the treatment group showed a significantly higher incidence of events whether drop outs were included or excluded (p < 0.025). CONCLUSION: Long term oral treatment with 15 mmol magnesium daily doses not reduce the incidence of cardiac events in survivors of an acute myocardial infarction and, indeed, seems to increase the risk of developing a cardiac event. Consequently, this treatment cannot be recommended as secondary prophylaxis for such patients.

[Severe obstructive lung disease. The effect of the calcium antagonist isradipine on working capacity, pulmonary function, morbidity and survival]. / Svaer, obstruktiv lungelidelse. Effekten af calciumantagonisten isradipin på arbejdskapacitet, lungefunktion, morbiditet og overlevelse.

Several studies have reported beneficial haemodynamic effects of calcium antagonists in the treatment of patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension. Such effects include a decrease in pulmonary vascular resistance, an increase in cardiac output, and an increase in oxygen delivery, but the clinical implications of these effects remain uncertain. We therefore designed this first randomized, double-blind, placebo-controlled, long-term study to investigate the clinical effects of a calcium antagonist (isradipine) on patients with COPD. The aim of the study was to investigate the hypotheses that isradipine was able to increase working capacity and lung function, and decrease morbidity and mortality. During a 22-month observation of 52 patients with severe COPD no statistically significant differences between the isradipine group and the placebo group were found with regard to these parameters. It is concluded that the existing evidence does not justify the introduction of calcium antagonists as part of the routine treatment of COPD with pulmonary hypertension.

The effects of propranolol and verapamil on hyperthyroid heart symptoms and function, assessed by systolic time intervals.

The effects of acute and chronic administration of propranolol and verapamil on heart rate and systolic time intervals were studied in 10 hyperthyroid patients and 10 normal subjects, both groups without signs of cardiovascular or pulmonary disease. In normal subjects iv propranolol reduced heart rate significantly, and both drugs increased the total electromechanical systole significantly without difference between the drugs. This effect was insignificant when the drugs were given orally. In hyperthyroid patients both drugs reduced heart rate significantly in acute and chronic administration, and no difference between the two drugs was found. Neither drug altered cardiac contractility as assessed by systolic time intervals. These results indicate that the metabolic effects of thyroid hormone on contractility were unaltered and unblocked by the drugs. None of the participants developed signs of heart failure. Verapamil can thus be used as an alternative to propranolol in the treatment of tachycardia in hyperthyroidism.

Effect of oral calcium supplementation on blood pressure in patients with previously untreated hypertension: a randomised, double-blind, placebo-controlled, crossover study.

It has been claimed that calcium lowers BP. The present randomised, double-blind, placebo-controlled crossover study is the first to investigate the effect on BP of a high oral dose of calcium given for a long period to patients with previously untreated hypertension. Elemental calcium (2 g) was administered for 12 weeks interchanging with a period of 12 weeks of placebo. Twenty patients completed the protocol. There was no significant difference in change of BP during the period of additional calcium intake when compared with placebo (P = 0.33). The risk of not detecting a real BP-lowering effect of calcium of at least 3 mmHg was < 5%. No evidence for the existence of a subgroup of 'responders' was found. It is concluded that a high daily dose of calcium supplementation given for 12 weeks does not decrease BP in previously untreated patients with mild to moderate hypertension.