Hypertension optimal treatment (HOT) study: a brilliant concept, but a qualified success

BACKGROUND TO THE STUDY: The Hypertension Optimal Treatment (HOT) study was designed to answer two questions: whether low-dose aspirin (75 mg/day) is effective in the primary prevention of myocardial infarction, without an increase in cerebral haemorrhage in hypertensive patients whose blood pressure is well controlled, and whether there are additional benefits with a progressive reduction of diastolic blood pressure from 90 mmHg to below 80 mmHg. SUCCESSES: In a landmark outcome, low-dose aspirin was indeed shown to be effective in the primary prevention of myocardial infarction. Moreover, the study has shed light on many important issues for blood pressure lowering in the treatment of hypertension, providing an excellent demonstration that with aggressive combination therapy, the elevated blood pressure in hypertensive subjects can be lowered and maintained in the normotensive range in over 90% of cases. DISAPPOINTMENT: The biggest disappointment was that the intention to treat analysis failed to demonstrate a significant difference between the three randomized target blood pressure groups for the majority of cardiovascular events.     

Optimal blood pressure control in treated hypertensive patients. Report from the Department of Health Hypertension Care Computing Project (DHCCP)

BACKGROUND: We wished to determine the range of treated systolic (SBP) and diastolic blood pressure (DBP) associated with the best survival in hypertensive patients. METHODS AND RESULTS: We conducted a cohort study of patients enrolled in the DoH Hypertension Care Computer Project. Five specialist hypertension clinics (95% of patients) and general practitioners (5%) followed 6214 patients (3070 men and 3144 women) with an average age of 52 years for a mean of 107 months. Total, cardiovascular, ischemic heart disease, (IHD) and stroke mortality were the outcome measures. Age-adjusted relative hazard rates were calculated giving the effect on mortality of systolic or diastolic pressure being higher by 1 mm Hg. In men the optimal level of SBP for all four measures of mortality was the lowest pressure range observed, 92 to 133 mm Hg (median 127). For women the treated SBP range of 96 to 148 mm Hg (median 137) was associated with a low total mortality and also with low to moderate rates for IHD and stroke mortality. Relative hazard rates (P < .001) for IHD mortality were 1.010 for men and 1.013 for women and for stroke mortality were 1.018 and 1.021, respectively. The results were similar in men under and over the age of 60. SBP and DBP tended to be more important in younger than older women. For treated DBP in men, a pressure of 55 to 94 mm Hg (median 87) was associated with a low total mortality. The lowest stroke mortality in men was observed for a DBP range of 55 to 83 mm Hg (median 80) but with a tendency for an increase in IHD mortality. For women DBP < 95 mm Hg (range 55 to 94, median 87) also was associated with a low total mortality. IHD mortality in women was not closely related to treated DBP, relative hazard rate = 1.003, [95% confidence index (CI); 0.990,1.017] but the relative hazard rate for men was 1.011, (95% CI; 1.000, 1.022). The relative hazard rates for treated DBP and stroke were high at 1.035 and 1.028 for men and women, respectively (P < .001). IHD mortality increased in the one third of patients with the greatest fall in DBP on treatment, provided they were not initially in the one-third group with highest untreated DBP. CONCLUSIONS: The best overall survival was associated with a treated SBP of < 134 mm Hg in men and < 149 mm Hg in women and a treated DBP of < 95 mm Hg.     

Measures of blood pressure and myocardial infarction in treated hypertensive patients

OBJECTIVE: To identify entry characteristics associated with subsequent myocardial infarction in treated hypertensive patients. DESIGN: Nested case-control study and cohort study. SETTING AND PATIENTS: The 5730 participants (mean age 53 years; 61% male and 45% Caucasian) were selected from a worksite-based, union-sponsored, systematic hypertension control program from 1973 to 1992. METHODS: In the case-control study myocardial infarction cases were matched by age, sex, year of entry to the program, years of follow-up and previous treatment status (treated or untreated) with non-event subjects. Baseline clinical and biochemical characteristics were analyzed with regard to the outcome of myocardial infarction, using univariate and multivariate analyses, respectively, in case-control and cohort studies. RESULTS: During 5.43 years of follow-up the incidence of myocardial infarction was 6.75/1000 person-years. Univariate analysis indicated that myocardial infarction cases had higher cholesterol level and were more likely to have a previous history of diabetes than controls. The initial systolic blood pressure and pulse pressure of cases were significantly higher than in controls. Logistic regression models indicated that initial pulse pressure, either as a continuous or as a categorical variable, was the only measure of blood pressure independently associated with myocardial infarction after adjustment for other risk factors. Analysis of the experience of the total 5730 as well as 2445 previously untreated patients with a cohort study generated identical results. CONCLUSION: A large pulse pressure difference appears to be the most powerful measure available of initial blood pressure to identify, in advance, those hypertensive patients at greatest risk for a subsequent myocardial infarction.     

Comparative effects of atenolol versus celiprolol on serum lipids and blood pressure in hyperlipidemic and hypertensive subjects

Antihypertensive drugs may affect serum lipoprotein levels in mixed populations but data in hyperlipidemic patients are scanty. Atenolol versus celiprolol effects on serum lipoproteins were compared in 159 hyperlipoproteinemic hypertensive patients. This was a randomized, double-blind, parallel-group, positive-controlled multicenter trial with centralized lipoprotein laboratory and diet constancy monitoring. Blood pressure reduction and serum lipoprotein and apoprotein levels were monitored for 3 months. Both drugs reduced systolic and diastolic blood pressures. Atenolol had greater effects than celiprolol on diastolic pressure, but effects on systolic blood pressure were not different. Patients receiving atenolol had lower serum high-density lipoprotein cholesterol levels and higher low-density lipoprotein/high-density lipoprotein cholesterol ratios, whereas patients treated with celiprolol showed no contrasting changes. These differences in lipoprotein levels between drug treatment groups were statistically significant at weeks 9 and 12. The difference between drug treatments was also significant if the values of the 9- and 12-week visits were averaged. Patients taking atenolol had statistically significantly higher serum levels of total cholesterol, triglycerides and apoprotein B at 9 weeks. These divergent directional changes were consistent throughout and statistically significantly different between drugs.     

The renin-angiotensin-aldosterone system in hypertensive subjects. I-Analytical study of 124 patients (author's transl)

An analytical study of the renin-angiotensin-aldosterone system was made in 124 individuals with essential hypertension, aged from 25 to 55 years. The results obtained, with rigorous control to posture and sodium balance, indicate the existence of a number of subgroups of hypertensive subjects related to their renin activity and plasma aldosterone in the upright position. This classification thus makes possible comparison with patients suffering from secondary hypertension.     

White coat effect detected using self-monitoring of blood pressure at home: comparison with ambulatory blood pressure

The objective of the study was to investigate whether home blood pressure (HBP) is a reliable alternative to ambulatory blood pressure (ABP) for the detection of the white coat effect (WCE). Hypertensive patients were randomized to measure HBP for 2 weeks or ABP for 24 h. The alternative measurement was then performed. Clinic blood pressure (CBP) was measured in the beginning and end of the study. Subjects with a difference of > or = 20 mm Hg systolic or > or = 10 mm Hg diastolic BP between CBP and awake ABP or CBP and HBP, were classified as clinic reactors. A total of 189 patients completed the study (79 on stable antihypertensive treatment). There was no difference in the magnitude of WCE assessed using the ABP or the HBP method (mean discrepancy, systolic BP: -1.5 +/- 11.7 mm Hg, 95% CI -3.2, 0.2; diastolic BP: 0.9 +/- 7.0, 95% CI -0.1, 1.9). A strong association existed between WCE calculated using the HBP or the ABP method (r = 0.64/0.59 systolic/diastolic, P < .001). The proportion of patients classified as clinic reactors was identical using the HBP or the ABP method (25.9%). Agreement between methods in the classification of clinic reactors was found in 147 patients (78%). The sensitivity and specificity of the HBP method to classify correctly clinic reactors (ABP method used as the standard) were 57% and 85%, respectively, whereas its positive and negative predictive value were 57% and 85%. These results indicate that HBP is not appropriate as an alternative to ABP diagnostic testing in the detection of WCE. Nevertheless, HBP appears useful as a screening test for the detection of this phenomenon.     

Inadequate management of blood pressure in a hypertensive population

BACKGROUND: Many patients with hypertension have inadequate control of their blood pressure. Improving the treatment of hypertension requires an understanding of the ways in which physicians manage this condition and a means of assessing the efficacy of this care. METHODS: We examined the care of 800 hypertensive men at five Department of Veterans Affairs sites in New England over a two-year period. Their mean (+/-SD) age was 65.5+/-9.1 years, and the average duration of hypertension was 12.6+/-5.3 years. We used recursive partitioning to assess the probability that antihypertensive therapy would be increased at a given clinic visit using several variables. We then used these predictions to define the intensity of treatment for each patient during the study period, and we examined the associations between the intensity of treatment and the degree of control of blood pressure. RESULTS: Approximately 40 percent of the patients had a blood pressure of > or =160/90 mm Hg despite an average of more than six hypertension-related visits per year. Increases in therapy occurred during 6.7 percent of visits. Characteristics associated with an increase in antihypertensive therapy included increased levels of both systolic and diastolic blood pressure at that visit (but not previous visits), a previous change in therapy, the presence of coronary artery disease, and a scheduled visit. Patients who had more intensive therapy had significantly (P<0.01) better control of blood pressure. During the two-year period, systolic blood pressure declined by 6.3 mm Hg among patients with the most intensive treatment, but increased by 4.8 mm Hg among the patients with the least intensive treatment. CONCLUSIONS: In a selected population of older men, blood pressure was poorly controlled in many. Those who received more intensive medical therapy had better control. Many physicians are not aggressive enough in their approach to hypertension.     

Dietary L-arginine attenuates blood pressure in mineralocorticoid-salt hypertensive rats

The present study was designed to investigate the influence of dietary L-arginine supplementation on blood pressure and on ex vivo vascular reactivity in mineralocorticoid-salt (DOCA-salt) hypertensive rats. Systolic blood pressure and heart rate were determined throughout the experimental period in unanaesthetized rats. Plasma and urine electrolyte levels were measured. Vasoconstrictor response to noradrenaline and vasodilator responses to acetylcholine and sodium nitroprusside were evaluated in the isolated perfused mesenteric vascular bed. DOCA-salt hypertensive rats were divided into 2 groups: a control group and a treated group receiving 0.8% L-arginine supplementation in drinking water. Dietary L-arginine supplementation attenuated systolic blood pressure in conscious DOCA-salt hypertensive rats, but did not modify heart rate. Plasma calcium and sodium concentrations and urinary magnesium excretion were decreased by L-arginine supplementation. Noradrenaline-induced vasoconstriction decreased and acetylcholine-induced vasodilatation increased, whereas sodium nitroprusside-induced vasodilatation was not modified, in the L-arginine-supplemented rats. It is concluded that dietary L-arginine supplementation in the diet lowers systolic blood pressure in DOCA-salt hypertensive rats, probably through vascular action.     

Effects of solcoseryl on the cerebral blood flow, intracranial pressure, systemic blood pressure and EEG in acute intracranial hypertensive cats (author's transl)

The experiment was performed on 86 cases under intraperitoneal pentobarbital anesthesia. One balloon was placed in the extradural space of right frontal region, and the other balloon was placed in the left extradural space and the intracranial pressure was measured. A needle was stereotaxically inserted into the subcortical area in order to measure the cerebral blood flow. Systemic blood pressure was recorded by inserting a catheter into the femoral artery, and electrocorticogram was also recorded. An expanding intracranial lesion was made by inflating the extradural balloon with physiological saline. The animals were arbitrarily divided into two groups.: 1) light or moderate groups which intracranial pressure before the injection of drug was below 400 mmH2O. 2) severe groups above 400 mmH2O. After the maintenance of the pressure, Solcoseryl was infused intravenously. The investigation was focused to observe whether Solcoseryl reveales any potent effect on cerebral blood flow, intracranial pressure, systemic blood pressure and on electroencephalogram in acute intracranial hypertension. Results 1) Intravenous injection of Solcoseryl had the effect of lowering intracranial pressure in the light or moderate and severe groups. Particularly, dose of 80 mg/kg showed the marked effect, though with a rebound phenomenon in the light or moderate groups. Furthermore, the effect was more marked and lasting by drip infusion of Solcoseryl and also by intravenous injection of Solcoseryl after pretreatment with hydrocortisone, and at this time no rebound phenomenon was recognized. 2) Solcoseryl had the effect of increasing the cerebral blood flow accompained with the lowering of intracranial pressure. 3) Systemic blood pressure was transiently lowered by the injection of Solcoseryl 20 mg/kg or 80 mg/kg and recovered immediately. 4) Solcoseryl had no effect on electroencephalogram in the severe groups. Conclusion On the basis of these results, it is rational to conclude that Solcoseryl could be superior agent render to lower intracranial pressure and to improve cerebral blood flow in acute intracranial hypertension.     

Heart rate and blood pressure variability in obese normotensive subjects

OBJECTIVE: To assess autonomic modulation of cardiovascular activity in massively obese subjects. DESIGN: Cross-sectional clinical study. SUBJECTS: 43 age-matched normotensive subjects: 15 moderately obese (body mass index (BMI) < 40); 14 massively obese (BMI > 40) and 14 nonobese controls (BMI < 26). MEASUREMENTS: Using power spectral analysis, heart rate and arterial pressure variability were determined at rest and after sympathetic stress (tilt). Two spectral components were analysed: a low-frequency (LF) component at around 0.1 Hz, predominantly reflecting sympathetic modulation and a high-frequency (HF) component at around 0.26 Hz, reflecting parasympathetic modulation. RESULTS: Spectral data for heart rate showed that the massively obese subjects had lower LF [mean +/- s.e.m.] normalized units (NUs) at rest (35.1 +/- 0.9) and after tilt (56.1 +/- 2.1), than the moderately obese subjects (LF NUs at rest 53.9 +/- 4.2, P < 0.001; LF NUs tilt: 66.8 +/- 5.6, P < 0.001) and nonobese control subjects (LF NUs at rest, 56.6 +/- 3.0, P < 0.001); (LF NUs tilt: 81.7 +/- 1.7, P < 0.001). Data for systolic arterial pressure variability measured at rest exhibited the inverse pattern, the massively obese group having higher mean LF values (LF mm Hg2 rest: 15.0 +/- 1.4; LF mm Hg2 tilt: 15.7 +/- 1.5) than the moderately obese group (LF mm Hg2 rest 3.2 +/- 0.7, P < 0.001; LF mm Hg2 tilt: 7.2 +/- 2.0, P < 0.001) and than the nonobese control subjects (LF mm Hg2 rest 3.5 +/- 0.5, LF mm Hg2 tilt 8.5 +/- 0.8, P < 0.001). Regression detected a significant association between BMI and LF of systolic pressure (beta = 0.364; P = 0.0007), In LF of heart rate (beta = -5.555; P = 0.00001) and very low frequency (VLF) of diastolic pressure (beta = -3.305; P = 0.0020). CONCLUSION: Obesity seems to increase sympathetic modulation of arterial pressure, but diminishes modulation of heart rate. Because our obese subjects had high plasma noradrenaline levels, their low LF power of heart rate could reflect diminished adrenoceptor responsiveness.     

Sympathetic activity and blood pressure in normotensive and hypertensive patients undergoing ophthalmic surgery under electrostimulation anaesthesia (author's transl)

Plasma adrenaline, noradrenaline, blood pressure and heart rate were determined in 10 normotensive and 10 hypertensive patients undergoing ophthalmic surgery under electrostimulation anaesthesia. Venous blood samples for the determination of the catecholamines by a spectrofluorometric method were taken 30 min after premedication and 45 min after surgical incision. The catecholamine concentrations showed no significant differences neither by comparing the normotensive patients with the hypertensive patients nor by comparing the values during operation with them after premedication in each group. However, in the hypertensive patients blood pressure showed a higher increase during operation than in the normotensive patients.     

The effect of caffeine on ambulatory blood pressure in hypertensive patients

Because the potential impact of habitual caffeine intake on blood pressure is a controversial issue, a study was carried out to explore the relationship between caffeine and various humoral factors that could account for a coffee-induced rise in blood pressure. Twenty-three hypertensive patients who refrained from caffeine for 2 to 3 weeks were given 250 mg oral caffeine powder dissolved in water. Blood pressure was recorded every 15 min by blood pressure monitor. Caffeine blood level, renin and endothelin were measured before and 1, 2, 3, and 6 h after caffeine intake. Urinary electrolytes and catecholamines were measured under caffeine influence (period I), and for the next 6 h (period II). A significant increase in systolic (P = .017) and diastolic blood pressure (P = .023) occurred in 13 subjects who were 58 +/- 10.4 years old. Nonresponders were younger (44.5 +/- 15.8 years). A statistically significant decrease in heart rate was seen during the first hour after caffeine intake in both responders (P = .008) and nonresponders (P = .004). Marked diuresis and natriuresis were observed during period I in both groups. Renin and endothelin levels were unchanged. Although chronic studies point to development of tolerance to long-term caffeine ingestion, acute studies like the one described are essential to obtain data on the immediate effects that can be of practical importance, especially in the elderly.     

Cardiac adaptation to increased systemic blood pressure in borderline hypertensive men

Two women, aged 28 and 32, presented with primary infertility and severe dysmenorrhea. The younger woman developed recalcitrant and recurrent firm vaginal, cervical and possibly endometrial lesions over a period of six years; the older patient had similar material in the cervix, endometrium and a fallopian tube. The lesions were composed of amorphous eosinophilic hyaline or necrotic material, shown by histochemical and immunoperoxidase stains to be partly fibrin. Pathologic examination showed that the lesions were similar to those of ligneous (pseudomembranous) conjunctivitis, a rare disease that may occasionally affect the lower female genital tract. However, neither patient had eye disease, and ligneous conjunctivitis has not previously been reported to involve the upper genital tract. Endometrial and tubal involvement could readily explain primary infertility and dysmenorrhea in these patients.     

Diurnal blood pressure patterns in normotensive and hypertensive children and adolescents

As abnormalities in diurnal ambulatory blood pressure (BP) have been associated with hypertensive target organ damage in adults, we investigated the diurnal systolic BP (SBP) and diastolic BP (DBP) patterns of 54 normotensive children, age 13.4 +/- 3.0 years, and 45 untreated borderline and mildly hypertensive children, age 14.4 +/- 2.6 years. Subjects wore the SpaceLabs 90207 ambulatory BP monitor for 24 h. BP was measured q 15 min from 08.00-21.00 h then q 30 min from 21.00-08.00 h. Nocturnal BP fall, the night-day ratio and cusum derived measures were calculated from time-weighted daytime and night-time SBP and DBP. The groups were compared using analysis of covariance with adjustment for age, race, gender and body mass index. The influence of age, gender and race on the diurnal BP profile was also examined. Nocturnal SBP fall was greater in hypertensive compared to normotensive subjects (17.1 +/- 6.7 vs 14.6 +/- 7.1 mm Hg; unadjusted mean +/- s.d., P = 0.022). Normotensive and hypertensive groups did not differ in nocturnal DBP fall or SBP or DBP night-day ratio. Race appeared to influence the diurnal BP pattern as black subjects had less nocturnal SBP fall (12.9 +/- 6.9 vs 17.1 +/- 6.5 mm Hg; P < 0.005) and a higher night-day SBP ratio (90.1 +/- 5.3 vs 86.7 +/- 4.6%; P < 0.005) than white subjects. In conclusion, hypertensive children and adolescents have a similar diurnal BP pattern as their normotensive counterparts, except that the entire BP profile is shifted upward with a greater absolute fall in SBP at night. Race also appears to influence the diurnal BP profile of normotensive and hypertensive children and adolescents.     

Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group

BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.     

Self-monitoring of blood pressure at home: how many measurements are needed?

Inappropriate sinus tachycardia and atrial arrhythmias have been reported after radiofrequency ablation. Previous studies have suggested that cardiac denervation is a possible explanation for these rhythm disturbances. The aim of this study was to investigate possible alterations in autonomic innervation of the heart after ablation using the techniques of heart rate variability (HRV) analysis and metaiodobenzylguanidine (I-123 MIBG) scintigraphy. The subjects of this study were 30 consecutive patients aged 25 to 40 years, without structural heart disease, who underwent radiofrequency ablation of atrioventricular nodal slow pathways, and posteroseptal and left lateral accessory pathways because of symptomatic recurrent reentrant tachycardias. Time and frequency domain analysis of HRV after ablation revealed a significant reduction in the indexes of the mean of all 5-minute standard deviation of RR intervals (p = 0.042), low frequency (p = 0.0005), and total frequency (p = 0.008) compared with preablation values in the group of patients who underwent atrioventricular nodal slow pathway ablation. Patients who underwent ablation of a posteroseptal accessory pathway also had significant attenuation of the indexes of standard deviation about the mean RR interval (p = 0.03), standard deviation of 5-minute mean RR intervals (p = 0.006), and low-frequency (p <0.0001), and high-frequency (p <0.0001) components. Significant I-123 MIBG map defects, indicating efferent cardiac sympathetic denervation, were also found in the same groups of patients: atrioventricular nodal group (p = 0.0024), posteroseptal accessory pathway group (p = 0.0007). None of the above changes in HRV and 123-I MIBG scintigraphy were seen in patients who underwent ablation of left lateral accessory pathways. We conclude that radiofrequency ablation in the anterior, mid-, and posterior regions of the low intraatrial septum may disrupt sympathetic fibers located in these regions, causing cardiac sympathetic denervation. The density of these fibers appear to be less along the left atrioventricular groove.     

Bismuth concentration in blood and urine of children treated with ventrisol (polfa) preliminary study

The bismuth concentration was measured in the blood and urine of 21 children from 8 to 17 years old (13.12 +/- 2.67) treated with Ventrisol (Polfa)-tripotassium dicitrato bismuthate (TDB). One tablet of TDB-equivalent to 120 mg Bi2O3. One tablet was given orally to the patients four times a day. Blood and urine was taken for measurement of bismuth concentration in the morning, on fasting, before the administration of Ventrisol on the 6-8 days, the 27-28 days of the therapy and in the 4-5, 8-9 weeks after TDB therapy. The reason for TDB treatment was chronic gastritis and/or duodenal ulcers, which were diagnosed by endoscopic examination. No bismuth in the blood and a very low concentration in the urine were determined in 19 children before TDB treatment. After 6-8 days of TDB treatment the bismuth concentration in the blood was 40.85 +/- 31.05 micrograms/L and 75.11 +/- 82.07 micrograms/L in the urine. In the 27-28 days of the treatment the bismuth concentration in the blood was 37.67 +/- 25.06 micrograms/L, and 163.56 +/- 181.86 micrograms/L in the urine. In the 4-5 weeks after the TDB treatment the bismuth concentration in the blood was 7.77 +/- 10.56 micrograms/L, and 15.72 +/- 9.87 micrograms/L in the urine. The bismuth concentration level in the urine rose together with the rise of the bismuth concentration level in the blood, the correlation factor was r = 0.68. No symptoms of side effects caused by the TDB treatment were observed. Before the treatment a high bismuth concentration was found in the blood of two patients. These cases are discussed later.