Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia.

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.

Racial differences in hemodynamic responses to environmental thermal stress among adolescents.

BACKGROUND: Previous studies by our laboratory and others have shown that blood pressure (BP) responses to many short-term laboratory stressors are greater in black than in white children. We sought to determine the cardiac and vascular contributions to these differences in BP reactivity and whether racial differences in vascular reactivity involve excessive vasoconstriction or deficient vasodilation. METHODS AND RESULTS: We evaluated BP, heart rate, and impedance cardiographic measures of preejection period (PEP) and total peripheral resistance (TPR) in healthy black (n=76) and white (n=60) adolescents (mean age, 14.8 years) during passive exposure to a vasoconstrictive cold chamber (8 degrees C to 10 degrees C) and a vasodilatory heat chamber (40 degrees C to 42 degrees C). Results indicated greater decreases in PEP and increases in TPR in blacks than whites during cold exposure (P<0.05) but no group differences during heat exposure. Covariance analyses indicated that the racial differences during cold exposure probably reflected greater beta-adrenergic cardiac reactivity and alpha-adrenergic vasoconstrictive reactivity in blacks than whites. CONCLUSIONS: Blacks and whites exhibited comparable myocardial and vasodilatory responses to heat stress, but blacks exhibited heightened myocardial and vasoconstrictive reactivity to cold stress. These results suggest that the locus of racial differences in vascular reactivity involves vasoconstrictive rather than vasodilatory function. The pattern of racial differences during cold stress raises the possibility that both myocardial and vasoconstrictive mechanisms may contribute to the increased risk of hypertension in blacks.

Pulmonary/systemic flow ratio in children after cavopulmonary anastomosis.

OBJECTIVES: This study attempted to provide a formula for calculation of the pulmonary/systemic flow ratio in children after bidirectional cavopulmonary anastomosis. BACKGROUND: With the bidirectional cavopulmonary anastomosis, only the superior vena cava blood is oxygenated by the lungs. The inferior vena cava flow recirculates into the systemic circulation. The ratio of these flows will determine systemic arterial saturation. METHODS: According to the Fick principle, 1) Systemic cardiac output (liters/min) = Pulmonary venous flow + Inferior vena cava flow; 2) Systemic blood oxygen transport (ml/min) = Pulmonary venous blood oxygen transport + Inferior vena cava blood oxygen transport. By substituting the first equation into the second, Pulmonary/systemic flow ratio = (Systemic saturation - Inferior vena cava saturation)/(Pulmonary venous saturation - Inferior vena cava saturation). RESULTS: We applied the third formula to data obtained from 34 catheterizations in 29 patients after bidirectional cavopulmonary anastomosis. Mean [+/- SD] age at operation was 1.70 +/- 1.43 years, and mean age at catheterization was 2.95 +/- 1.65 years. The pulmonary/systemic flow ratio calculated for all 29 patients was 0.58 +/- 0.09. Of 17 patients with aortography, 10 had systemic to pulmonary collateral vessels. Patients with collateral vessels had a significantly higher pulmonary/systemic flow ratio (0.61 +/- 0.07 vs. 0.53 +/- 0.07, respectively, p < 0.02) and systemic saturation (88 +/- 4% vs. 82 +/- 4%, respectively, p < 0.002) than those without collateral vessels. The pulmonary/systemic flow ratio in those patients with no collateral vessels was similar to the previously reported echocardiographically derived superior vena cava/systemic flow ratio in normal children. CONCLUSIONS: The pulmonary/systemic flow ratio after bidirectional cavopulmonary anastomosis can be calculated. Pulmonary blood flow in these patients determines systemic saturation and accounts for the majority of venous return in young children.

Race, sex, and family history of hypertension and erythrocyte sodium pump [3H]ouabain binding.

We studied the binding properties of [3H]ouabain to erythrocytes from normotensive children (n = 83) between the ages of 10 and 18 years (mean resting arterial pressure: 102/57 mm Hg) from normotensive and essential hypertensive parents. Arterial blood pressures of 101/57 and 104/57 mm Hg (subjects with normotensive and hypertensive parents, respectively) were not significantly different between the two groups. Forty-four children had normotensive parents and 39 had hypertensive parents, 51 were white and 32 were black, and 41 were girls and 42 were boys. By using the [3H]ouabain-binding technique, we determined the density of sodium pump sites and the equilibrium dissociation constants in erythrocytes from these children. Possible effects of race, sex, or parental hypertension status on pump sites and dissociation constants were tested with a three-way analysis of variance (ANOVA). Race had a major effect on the dissociation constant: blacks had a significantly higher value than did whites (p = 0.002). We also found a race by sex by parental hypertension status interaction (p = 0.04) with black girls with hypertensive parents having the highest value. There was no effect of race, sex, or status on sodium pump site density. Age, height, weight, resting arterial blood pressure, and plasma Na+ and K+ concentrations did not correlate with the dissociation constants. These data suggest that, among the groups we studied, black girls with hypertensive parents had erythrocytes with the lowest binding affinity for ouabain.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethnicity, pressor reactivity, and children's blood pressure. Five years of observations.

During the 5 years of this investigation, resting blood pressure and pressor reactivity were measured in 292 white children and 46 black children in 1987, 1988, 1989, and 1991. In 1987, all children were in the third grade; in 1991, the children were in the seventh grade. Reactivity was assessed with a standardized psychological stressor, a television video game. Children displayed significant stability of absolute blood pressure and heart rate reactivity between grades 3 and 7. At all examinations, black children demonstrated blood pressure reactivity that was significantly greater in magnitude (both absolute level and change from resting measurements) than that of white children. Black children exhibited significantly greater heart rate reactivity only when defined as change from the resting measurements; absolute levels of heart rate reactivity were comparable for blacks and whites. For black children, blood pressure reactivity in 1987 was the strongest predictor of resting blood pressure (both systolic and diastolic) in 1991. Among white children, resting blood pressure was the strongest predictor of future resting blood pressure. Further research is needed to determine if ethnic differences in children's pressor reactivity are associated with ethnic differences in the prevalence of hypertension.

Consistency of ethnic differences in children's pressor reactivity. 1987 to 1992.

In this prospective investigation, all children enrolled in the public third-grade classrooms of an entire county (n = 474) had blood pressure measured both at rest and during a stressful television video game. Examinations were repeated in 4 subsequent years when cohort children as well as newly enrolled children were in grades 4, 5, 7, and 8. Both cross-sectional and longitudinal analyses indicated that black children demonstrated significantly greater systolic and diastolic pressor reactivity than white children. These data suggest that ethnic differences in children's pressor reactivity presage ethnic differences in adulthood hypertension.

Patterns of sodium excretion during sympathetic nervous system arousal.

The purpose of this study was to examine Na+ handling and regulation during 1 hour of behaviorally induced sympathetic nervous system (SNS) arousal followed by 2 hours of recovery. Two patterns of response were observed among experimental subjects, despite similar changes in blood pressure and heart rate. In one group (n = 19), Na+ excretion increased significantly during SNS arousal, which then decreased significantly during recovery (12.3 versus 16.0 versus 13.1 meq/hr, baseline, SNS arousal, recovery, respectively). Changes in Na+ excretion were correlated with changes in creatinine clearance from baseline to SNS arousal (r = 0.54) and SNS arousal to recovery (r = 0.58), and were accompanied by significant increases in plasma renin activity (1.5 versus 2.0 ng/ml/hr) and aldosterone (8.5 versus 10.3 ng/ml/hr) from baseline to SNS arousal. Na+ excretion decreased during SNS arousal in the other group of subjects (n = 17) and remained below baseline levels during recovery (16.2 versus 12.7 versus 11.9 meq/hr). These changes were associated with significant decreases in creatinine clearance from baseline to recovery (138 versus 121 ml/min/1.73 m2) and significant increases in plasma renin activity from baseline to SNS arousal (1.3 versus 2.2 ng/ml/hr) but not in aldosterone. Control subjects (n = 24) maintained baseline levels of each variable throughout the procedure. These results suggest that individuals differ in Na+ handling and regulation during behavioral arousal. Decreases in Na+ have been reported previously in humans and animals at risk for the development of hypertension.

Race and cardiovascular reactivity. A replication.

In a previous study, we reported that black children demonstrated greater cardiovascular reactivity than did white children to the psychological stress of a television video game. Reliance on urban volunteers and the wide age range of the children may have limited conclusions concerning the generalizability of those results. In the present study, 481 of 484 children enrolled in the third grade of the public schools of an entire rural county in Tennessee were examined with the same video game procedure used previously. Results indicated greater heart rate and blood pressure reactivity among black children than among white children. Thus, the previous results were replicated. The greater prevalence of hypertension among black adults may relate to the greater reactivity among black children; reactivity may be either a marker or a mechanism in the development of hypertension.

Race and cardiovascular reactivity. A neglected relationship.

The magnitude of the cardiovascular response to stress has been implicated in the pathogenesis of cardiovascular disease. Psychological stress procedures have received increased usage as an alternative to expensive physical (exercise) stress procedures. In the present investigation, 213 healthy, black or white, male or female children between the ages of 6 and 18 years were exposed to the psychological stress of a video game. The video game challenge was administered by a black or a white experimenter and was played under three levels of increasing stress, 1) personal challenge, 2) experimenter's challenge, and 3) experimenter's challenge accompanied by a financial incentive, while blood pressure and heart rate were monitored. Results indicated that the video games provoked significant and incremental cardiovascular reactivity across the games. Black children demonstrated significantly greater reactivity than white children; the racial difference was more reliably observed for systolic and diastolic blood pressure than for heart rate. Furthermore, the race of the experimenter exerted a significant effect and often interacted with the race of the child, such that greater reactivity occurred in same-race pairings than in mixed-race pairings. These results suggest that reactivity is affected by an individual's race and social milieu and that reactivity may be one mechanism responsible for the greater prevalence of hypertension among blacks.

Race and gender influence ambulatory blood pressure patterns of adolescents.

The purpose of this study was to examine ambulatory blood pressure and heart rate patterns in healthy, normotensive adolescents and to determine the influence of race and gender on these patterns. Ambulatory blood pressure recordings were performed on 199 adolescents; 42 were black males, 55 were white males, 65 were black females, and 37 were white females. The mean age (+/- SD) was 13 +/- 2 years. Blood pressure readings were obtained with an automatic, noninvasive recorder. Black adolescents and white adolescents had similar blood pressures while awake (116/69 vs. 116/69 mm Hg), with boys having higher levels of systolic blood pressure (118 vs. 114 mm Hg) and comparable levels of diastolic blood pressure (69 vs. 69 mm Hg) relative to girls. The patterns while the adolescents were asleep, however, were different. White boys (106 mm Hg), white girls (105 mm Hg), and black girls (105 mm Hg) had similar systolic blood pressures during sleep. Black boys (112 mm Hg), however, had significantly higher systolic blood pressures while asleep. Black adolescents, as a group, had significantly higher diastolic blood pressures than white adolescents while asleep (64 vs. 61 mm Hg). Changes in blood pressure from awake to asleep were not related to changes in heart rate. Results of this study indicate that both race and gender are important determinants of the diurnal pattern of blood pressure and heart rate in adolescents.

Aerobic fitness and the diurnal rhythm of blood pressure in adolescents.

We examined the effects of aerobic fitness and race on the diurnal rhythm of blood pressure of 175 healthy adolescents who performed a cycle ergometer maximal exercise test while oxygen consumption was measured. A median split of maximum oxygen consumption for boys and girls separately classified them as either "more-fit" or "less-fit" subjects. Ambulatory blood pressure recordings were also performed, and the data were analyzed for means while subjects were awake and asleep. Less-fit black boys had higher systolic pressures than more-fit black boys while awake (124 vs. 115 mm Hg; p less than 0.009) and asleep (117 vs. 108; p less than 0.001). Less-fit black boys also had higher systolic pressures than less-fit white boys while awake (114; p less than 0.002) and asleep (105; p less than 0.001), and they had higher systolic pressures than more-fit white boys while asleep (105; p less than 0.01). Less-fit black girls had higher systolic pressures than more-fit black girls while awake (116 vs. 109; p less than 0.004) and asleep (109 vs. 100; p less than 0.001). Less-fit black girls also had higher diastolic pressures than more-fit black girls while awake (71 vs. 66; p less than 0.002) and asleep (66 vs. 61; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium excretion and racial differences in ambulatory blood pressure patterns.

The influence of Na+ excretion and race on casual blood pressure and ambulatory blood pressure patterns was examined in a biracial sample of healthy, normotensive children and adolescents (10-18 years; n = 140). The slopes relating 24-hour urinary Na+ excretion to systolic blood pressure were different for both black and white subjects for casual blood pressure (p less than 0.001) and blood pressure during sleep (p less than 0.03). For casual blood pressure, the slope was significant for black subjects (beta = 0.17; p less than 0.001) but not for white subjects. For blood pressure during sleep, the slope was again significant for black subjects (beta = 0.08; p less than 0.01) but not for white subjects. Na+ excretion was also related to awake levels of systolic blood pressure for black subjects (beta = 0.08, r = 0.36; p less than 0.01), although the slopes for both black and white subjects were not significantly different. Further analyses indicated the results were not due to racial differences in 24-hour urinary K+ excretion. However, plasma renin activity was marginally related to Na+ excretion in white subjects (r = 0.22; p less than 0.06) but not black subjects, a finding that is consistent with previous studies. Na+ excretion was not associated with diastolic blood pressure or heart rate in either group under any condition. The results of this study support research that has demonstrated a stronger relation between Na+ handling and casual blood pressure in black subjects and extend these findings to blood pressure while the subject is both awake and asleep.

Racial differences in the age-related increase in left ventricular mass in youths.

We determined the factors related to left ventricular mass adjusted for body size in 60 black (mean age, 13 +/- 2 years) and 40 white (mean age, 14 +/- 2 years) normotensive youths. The factors examined included age, sex, systolic blood pressure, diastolic blood pressure, plasma renin activity, plasma aldosterone concentration, and sodium and potassium intake as determined by 24-hour excretion. Sex (beta = 13.3, P < .003), age (beta = 2.88, P < .001), and systolic blood pressure (beta = 0.41, P < .02) were independent predictors in the sample as a whole, accounting for 37% of the variance of left ventricular mass adjusted for height. Separate analyses were performed for black and white subjects. In the black subjects, age (beta = 4.4, P < .004) followed by sex (beta = 11.85, P < .02) were independent factors, accounting for 43% of the variance of left ventricular mass adjusted for height. In contrast, in white subjects systolic blood pressure (beta = 0.4, P < .003) followed by sodium excretion (beta = 0.13, P < .05) were independent factors, with gender (beta = 8.89, P < .07) tending to account for 36% of the variance. Similar results were observed for left ventricular mass adjusted for body surface area. In conclusion, the age-related increase in adjusted left ventricular mass in black but not white youths may in part account for the early development of cardiovascular disease among the black population.

Spontaneous closure of small ventricular septal defects: ten-year follow-up.

The natural history of small ventricular septal defect (VSD) was studied in 50 infants for up to 10.5 years. The VSD closed spontaneously in 34 patients. Life-table analysis of the data showed that by 10 years of age, 75% of small VSD will close spontaneously; the figure is higher for defects in the muscular septum (83%).

Ambulatory blood pressure recordings in children and adolescents.

OBJECTIVE: To provide reference data for ambulatory blood pressure monitoring (ABPM) and to determine the influence of age, sex, and race on these values. METHODS: ABPM was performed on 300 healthy, normotensive boys and girls between the ages of 10 and 18 years, including 160 boys and 140 girls, of whom 149 were white and 151 were black. Mean systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) while awake and during sleep were calculated for black and white boys and girls aged 10 to 12 years, 13 to 15 years, and 16 to 18 years. RESULTS: Boys compared with girls 10 to 12 years of age had higher mean (+/- SD) SBP (115 +/- 9 vs 112 +/- 9 mm Hg; P < .01) and DBP (67 +/- 7 vs 65 +/- 5 mm Hg; P < .01) while awake. Boys compared to girls 13 to 15 years of age had higher SBP while awake (116 +/- 11 vs 112 +/- 8 mm Hg; P < .01). Boys compared with girls 16 to 18 years of age had higher SBP while awake (125 +/- 12 vs 111 +/- 9 mm Hg); P < .01) and during sleep (116 +/- 11 vs 106 +/- 9 mm Hg). Comparisons within sex showed similar changes with age for boys and girls. Blacks compared with whites 13 to 15 years of age had higher SBP during sleep (109 +/- 11 vs 105 +/- 10 mm Hg; P < .01), and blacks compared with whites 16 to 18 years of age had higher DBP during sleep (66 +/- 7 vs 58 +/- 6 mm Hg; P < .01). Comparisons across age groups within race showed that blacks 16 to 18 years of age had higher SBP during sleep than blacks 10 to 12 years of age (109 +/- 11 vs 104 +/- 10 mm Hg), and higher DBP during sleep (66 +/- 7 mm Hg; P < .01) than blacks 10 to 12 years of age (61 +/- 7 mm Hg; P < .01) and 13 to 15 years of age (61 +/- 8; P < .01 mm Hg). The changes with age were not significant for white subjects. CONCLUSION: These results provide age-specific reference data for ABPM in youths. These values differ by sex (boys more than girls) and race (Blacks more than Whites).

Syncope recurrence in children: relation to tilt-test results.

OBJECTIVES: To examine the intermediate-term outcome of children with syncope and its relationship to tilt test. DESIGN: This was a retrospective study of 45 children. In 20, the tilt test was negative. Follow-up with respect to the recurrence of syncope was obtained via chart review, a mailed questionnaire, or telephone interview. RESULTS: Follow-up data were available on 15 children whose tilt test was negative and on all 25 tilt-test positive children. Recurrent syncope was significantly greater in the positive-tilt children (13 of 25) than the negative-tilt children (2 of 15). There was no difference between the syncope-free group and the recurrent syncope group or between the tilt-positive and tilt-negative groups with respect to age at initial syncope, duration of symptoms, age at tilt test, and duration of follow-up. Children with a positive tilt test and those with recurrent syncope had more syncopal episodes before their evaluation than either the group with a negative tilt test or the group with no recurrent syncope, respectively. CONCLUSIONS: Syncope may recur after either a negative or a positive tilt test. The recurrence rate, however, is higher for the tilt-positive children.

Ambulatory blood pressure patterns in children and adolescents: influence of renin-sodium profiles.

A renin-sodium nomogram for normotensive children and adolescents was developed at our institution. The ambulatory blood pressure patterns of subjects classified by the nomogram were then compared. A biracial sample of 159 children and adolescents were classified as having a low, intermediate, or high renin-sodium profile based on the relationship between their plasma renin activity and 24-hour urinary sodium excretion. Casual (106/58 vs 107/61 vs 106/62 mm Hg) and awake (116/69 vs 117/69 vs 116/70 mm Hg) blood pressure values were comparable among subjects with low, intermediate, and high renin-sodium profiles. Subjects with high renin-sodium profiles, however, had a smaller decline in systolic blood pressure with sleep than did subjects with low renin-sodium profiles (7 vs 11 mm Hg; P less than .04), and higher diastolic blood pressure readings during sleep than subjects with intermediate renin-sodium profiles (65 vs 62 mm Hg; P less than .05). Subjects with high renin-sodium profiles also had greater variance of diastolic blood pressure readings during sleep than either subjects with low renin-sodium profiles (P less than .01) or those with intermediate renin-sodium profiles (P less than .02). The blunted nocturnal decline and increased nocturnal variance of blood pressure among subjects with high renin-sodium profiles may be a marker or mechanism for the future development of essential hypertension.

The PAPERCUFF, a new disposable blood pressure cuff.

We demonstrated the accuracy of a new disposable BP cuff (CAS PAPERCUFF) compared with 2 widely used cuffs. The PAPERCUFF should limit the possibility of spread of infection and reduce costs.

Role of the renin-angiotensin-aldosterone system in hypertensive children with coarctation of the aorta.

To investigate the role of the renin-angiotensin-aldosterone system as a cause of hypertension, 20 hypertensive patients with coarctation of the aorta were studied during normal and low sodium intake and after diuresis with flurosemide. Eight patients with essential hypertension and 13 control subjects were similarly studied. Plasma renin activity values in patients with coarctation were similar to those in patients with essential hypertension and in control patients during normal and low sodium diets. However, after the administration of furosemide, plasma renin activity values were significantly higher in the patients with coarctation than in the other two groups (P less than 0.005 and less than 0.01, respectively). The values for urinary aldosterone, plasma volume and extracell fluid volume (bromide space) were increased in patients with coarctation during both normal and low sodium intake. These renin and aldosterone responses and body fluid spaces in patients with coarctation suggest that their hypertension resembles a one-kidney Goldblatt model. The data help to better define the role of the renin-angiotensin-aldosterone system in the hypertension of coarctation and thus may help guide the clinician in therapeutic interventions.

Hemodynamic responses to supine exercise in children with left-sided cardiac disease.

Exercise, a physiologic stress, has been used in adults to unmask abnormalities of left ventricular hemodynamics not detectable at rest. Similar data in children are not available. An evaluation was made of the feasibility, safety and value of a graded upright and supine ergometer stress test to assess exercise hemodynamics during cardiac catheterization in 21 children with left-sided cardiac disease. The catheterization technique involved the simultaneous recording of intracardiac and great vessel pressures, thermodilution cardiac index and M mode echocardiograms of the left ventricular cavity. The method appears practical and safe. Although hemodynamic responses varied among clinical groups, the lack of control data currently prevents assessment of the value of this technique for long-term management.