The S o d i u m - P o t a s s i u m Blood Pressure Trial in Children Design, Recruitment, and Randomization: The Children and Adolescent Blood Pressure Program Orlando G6mez-Marin, MSc, PhD, Ronald J. Prineas, MD, PhD, and Alan R. Sinaiko, MD Department of Epidemiology and Public Health University of Miami School of Medicine (0. G.-M.; R.J.P) and Departments of Pediatrics and Pharmacology University of Minnesota Medical School (A. R. S.)
ABSTRACT: The Sodium-Potassium Blood Pressure Trial in Children (NaKS), is a clinical trial in a healthy, free living population of children and adolescents. It is designed to test the hypotheses that a reduction in dietary sodium and/or an increase in potassium intake will decrease the rate of rise in blood pressure during normal maturation in children and adolescents with high normal blood pressure. Screening was conducted in 19,452 students in grades 5-8 in Minneapolis and St. Paul between January 1986 and May 1987. After screening, 3,223 students were found to have blood pressures that fulfilled the initial eligibility criteria for the study, and of these, 643 (20.0%) attended the orientation meeting, i.e., the first clinic visit. A total of four clinic visits, designed to test the willingness and capability of the potential participants to comply with the study protocol were conducted prior to randomization. At the conclusion of the four prerandomization visits, 243 children (7.5% of the initially eligible children) agreed to be randomized to one of four trial groups: low-sodium diet; potassium supplement administration; placebo-treated control group; and a no-treatment control group (to test the effect of acclimatization on blood pressure measurements) that will not be seen after randomization until the 4-year termination of the study. The first participant was randomized into the study on June 17, 1986, and the last on December 29, 1987. The potassium and placebo capsules are administered double-masked. Participants will be examined and receive intervention instruction four times yearly for 4 years counted from the date of their randomization. All groups were comparable with regard to distribution of school district, sex, and race and with respect to baseline physical characteristics. Results from this study will provide information about the feasibility and effect of dietary intervention during childhood and adolescence on the prevention of essential hypertension. KEY WORDS: Clinical trial, hypertension, children, sodium, potassium
Address reprint requests to: OrlandoG6mez-Maffn, PhD, Departmentof Epidemiologyand Public Health (R669), University of Miami Schoolof Medicine, P.O. Box 016069, Miami, FL 33101. Received June 15, 1990; revisedJanuary 22, 1991.
408 0197-2456/91/$3.50
Controlled ClinicalTrials 12:408-423(1991) © ElsevierSciencePublishing Co., Inc. 1991 655 Avenueof the Americas, New York, New York10010
Sodium-Potassium BP Trial in Children: Design
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INTRODUCTION Blood pressure increases at a steady rate in children through early adolescence [1]. This increase follows a "tracking" pattern, in which children at a specific percentile of blood pressure distribution tend to maintain that position as they grow older [2-4]. It has been suggested that children tracking at the upper deciles of blood pressure distribution are at increased risk to develop essential hypertension as adults, and recent data support this conclusion [5]. With the incorporation of blood pressure measurement into the pediatric physical examination and availability of accurate blood pressure distribution curves from a number of epidemiologic surveys [1], it has become clear that mild elevations of blood pressure may be more common than previously recognized in children. Thus, the dual issues of (1) effectiveness of introducing strategies during childhood and adolescence to prevent essential hypertension and (2) the most appropriate approach to children with borderline or mild hypertension have become highly relevant to pediatric health care delivery, and there is a need to establish whether nonpharmacologic antihypertensive treatment is feasible, effective, and safe in these age groups. This article presents the rationale, study plan, and recruitment results for a randomized controlled trial designed to test the effects of dietary sodium restriction or oral potassium supplementation on the rate of rise of blood pressure during late childhood and adolescence. In particular, it describes the recruitment of a cohort of junior high school-aged children and their families subjected to a rigorous prerandomization protocol. Modification of dietary sodium and potassium is a potential alternative to pharmacologic treatment for prevention and control of hypertension. The direct relationship between sodium and blood pressure was established by the early work of Dahl and colleagues in animals [6] and humans [7]. Evidence from epidemiologic studies supports the contension that sodium intake influences blood pressure levels within a population [8]. On the one extreme are isolated, unacculturated groups that subsist on low sodium diets and do not experience either an increase in blood pressure with age or the occurrence of hypertensive disease [9]; in contrast, in countries such as the United States where more than 20% of the adult population is hypertensive [10], sodium intake is far in excess of the amount required to satisfy nutritional needs [11,12]. Sodium sensitivity can be documented in some adults and children with hypertension [13-15], as well as in a segment of the normotensive population [16]. It has been shown that dietary sodium restriction causes sigrlificant reductions in blood pressure in adults with mild to moderate diastolic hypertension [17], that the antihypertensive response is related to the degree of sodium restriction [18], that the need for antihypertensive drugs can be reduced by sodium restriction in individuals being treated for hypertension [19], and that more modest reductions in blood pressure occur in normotensives placed on sodium-restricted or reduced diets [20,21]. However, the outcome following sodium restriction is not uniform, and other studies have not been able to show similar changes in blood pressure [22-25]. The antihypertensive effect of potassium has been known for approximately 50 years but has been overshadowed by interest in the relationship between sodium and blood pressure [26]. Potassium supplementation is known
410
o. G6mez-Maffn et al. to induce natriuresis, decrease plasma renin activity, inhibit adrenergic nervous system activity, and cause direct vasodffatation of peripheral blood vessels. Epidemiologic studies have shown an inverse relationship between both blood pressure and stroke and the intake of potassium [27,28]. Clinical experience with adequate potassium treatment is limited. Short-term trials in adults have shown only modest success in reducing blood pressure [24,29]. Patterns of dietary sodium and potassium preference are established during infancy, and the intake of sodium by children approaches that of adults by the end of the first year of life [30]. Because sodium intake by children is far in excess of daffy requirements, reduction in sodium intake or an increase in the intake of potassium may have a substantial impact on blood pressure in this age group. A positive outcome from this clinical trial could have implications for future research on the development and utility of early intervention in essential hypertension.
STUDY DESIGN Objectives The primary objective of The Sodium-Potassium Blood Pressure Trial in Children (NaKS) is to test the hypotheses that a reduction in dietary sodium and/or an increase in potassium intake decreases the rate of rise of blood pressure during normal maturation in children and adolescents with high normal blood pressure. This trial will establish the feasibility of sodium reduction or potassium supplementation and their effect on blood pressure in this age group, and it will develop a database for evaluation of the long-term effect of sodium/potassium intervention on the natural history of blood pressure during the adolescent-adult transition period. At the conclusion of four clinic visits conducted prior to randomization, participants were randomly assigned in the ratio of 2:2:2:1 to one of the following groups: 1. Low Sodium Diet Group: Dietary sodium reduction to 70 mEq daffy sodium intake. 2. Potassium Chloride Group: Daffy potassium supplementation of I mEq/kg body weight (maximum 80 mEq/day) with capsules containing potassium chloride. 3. Placebo-Treated Group: Daffy intake of placebo capsules. 4. Nontreated Control Group: Nonintervention group. The nontreated control group was included not for comparison of treatment effect, but only to compare with the placebo group the effect on blood pressure measurement of "acclimatization" from regular clinic visits. The first participant was randomized into the study on June 17, 1986, and the last on December 29, 1987.
Study Groups Low sodium diet group. This group is not administered any capsules. Participants in the group are instructed to perform a gradual reduction of dietary
Sodium-Potassium BP Trial in Children: Design
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sodium to a level of 1,600 mg (70 mEq/day/family member), according to the contact schedule outlined in Table 1. At each of the five group sessions, families are separated into children and parent groups for an educational session and then reunited for a low-sodium refreshment period and discussion. This strategy has been shown to be superior for achieving compliance in trials in children [31]. In addition, two sessions, where children and parents meet together, are held for each family, and three telephone contacts are made to monitor progress, problem solve, and to offer support. At each 3monthly clinic visit during the 4-year maintenance phase of the trial, participants meet with a study interventionist for ongoing education, reinforcement, and support. To specifically determine dietary sodium intake, parents and children are instructed in record keeping using 3-day food records and sodium point tally sheets. The amount of sodium (mEq) consumed on each of 3 days is averaged, and this value is used for analysis. Compliance is assessed by analysis of the 3-day food records and electrolyte measurements in 24-hour urine samples.
Capsule groups. The capsule treatment is a double-masked design, with capsule content known only to the Data and Safety Monitoring Committee. Potassium Supplementation Group. The participants in this treatment group remain on their normal diets without any dietary sodium modification. In addition, they receive potassium supplementation calculated to increase their potassium intake above usual dietary levels by I mEq/kg body weight per 24 hours (maximum of 80 mEq per 24 hours). Potassium chloride intake is adjusted during the trial according to changes in body weight associated with growth. Potassium chloride is administered in capsules (Micro-K, 8 mEq or 600 mg KC1 per capsule, kindly supplied by Wyeth-Ayerst) containing film-coated microencapsulated KC1 crystals. The daily potassium requirement is divided into two equal amounts administered morning and evening with meals. At each 3-monthly visit, children in this group meet with a study interventionist. Compliance in the KC1 group is assessed by measurement of electrolytes in 24-hour urine samples and by pill counts at each visit. Placebo-Treated Group. Participants in this group are treated in an identical fashion to the potassium supplementation group. Table 1 Initial Contact Schedule for the Dietary Sodium Group Weeka Contact Content 1 Mail/phone Notification of group session and follow-up reminder call Low sodium seasonings 2 Group Daily sodium menu planning 3 Group Nutrition, label reading, and low-sodium lunches 4 Group 5 Individual Progress check 6 Phone Follow up on progress Eating out 7 Group Snack preparation workshop 9 Group 11 Phone Progress check Review and progress check 12 Individual "Weeks after randomization.
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Nontreated control group. After randomization, participants in this group are not seen by the staff for the 4-year duration of the trial. Their addresses and telephone numbers are updated yearly in the study files, and they are contacted by mail at birthdays and holidays. At the end of the study this group will be seen for a complete health status assessment.
Sample Size The design of this trial is a repeated-measures design with 17 measurements of blood pressure, height, and weight (every 3 months) and 9 measurements of sodium intake, and urinary sodium, potassium, chloride, calcium, magnesium, and creatinine (every 6 months). The main null hypothesis, i.e., there is no difference between treatment groups with respect to the rate of rise of blood pressure, will be tested by comparing the linear trends resulting from the orthogonal decomposition of the "group × time" interaction in a repeatedmeasures analysis of variance. Sample sizes needed to test the hypothesis with adequate power were initially calculated by considering the three treatment groups (Low Sodium Diet, Potassium Supplementation, and Placebo) and using longitudinal data from the Minneapolis Children's Blood Pressure Study [2,32] to estimate the standard error of the linear contrast. Since the three possible pairwise comparisons of linear contrasts are of interest, the sample size calculations were performed using one third of the nominal levels. Table 2 shows that, for example, a difference in rate of increase of blood pressure of 0.75 mm Hg/yr (i.e., difference of 3.0 mm Hg in blood pressure levels after 4 years of intervention) can be detected with 85% power at a nominal ot level of 0.05 with 61 participants in each of the three treatment groups.
Duration of the Trial Participants in this trial will be.evaluated over 4 years, counted from their date of randomization. Trials in adults using sodium reduction and/or potassium supplementation have been conducted over much shorter periods of
Table 2 Number of Subjects Required in Each of Three Treatment Groups to Detect Specified Pairwise Differences in Rate of Increase of Systolic Blood Pressure (mm Hg per year) at Given Power and a Levels Pairwise Differences in Rate of Increase of SBP (ram Hg/yr) c~ Levela 0.625 0.750 0.875 1.000 1.125 1.250 Power 0.80 0.01 106 73 54 41 32 26 0.05 79 55 40 31 24 20 0.85 0.01 118 81 60 46 36 29 0.05 89 61 45 35 27 22 0.90 0.01 132 91 67 51 41 33 0.05 102 70 52 40 31 25 0.95 0.01 156 108 80 61 48 39 0.05 123 85 63 48 38 31 ~Toadjust for multiplepairwise comparisons,the sample size calculationswere performedusing one third of these nominala levels.
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time, because the outcome of those trials, i.e., degree of antihypertensive response in individuals with significant hypertension, usually' can be determined within weeks or months. In contrast, evaluation of the effect of nonpharmacologic treatment on the gradual increase in blood pressure, characteristic of the first and second decades of life [2], was estimated to require a greater longitudinal commitment. In addition, the effectiveness of this intervention is dependent, in part, on allowing sufficient time to establish the behavioral changes required by each of the treatment groups. Therefore, the 4-year observation period was deemed necessary to assess the major hypotheses.
Recruitment of Participants Blood pressure measurement and eligibility. Participants for this trial were recruited from 5th, 6th, 7th, and 8th grade students in the Minneapolis and St. Paul public schools. During the period from January 1986 to May 1987, screening of blood pressure was conducted in schools during regular school days. Children had their blood pressure measured twice on the right arm and in the seated position by trained personnel, using a standard clinical sphygmomanometer and following a standardized protocol [32]. All children whose systolic blood pressure (mean of two measurements) equalled or exceeded the 70th percentile of age-specific distribution (Table 3) had their blood pressure measured on a second occasion (rescreening) under identical circumstances. All white, black, Hispanic, white/black, white/Hispanic, and black/Hispanic children whose blood pressure at rescreening was above 109 m m Hg for boys and 108 m m Hg for girls (i.e., approximately the upper 15% of all children screened) were invited to participate in the trial. Recruitment clinic visits. The children were seen at four separate visits prior to randomization. Each of these visits was held in the study clinic. The schedule of these clinic visits and the list of data collected at each of them are given in Table 4. Orientation Meeting (Clinic Visit 1, CV-1). All children eligible after rescreening received a letter inviting them to participate in the trial. The letter was followed, within 10 days, by a telephone call during which children were Table 3 Systolic Blood Pressure (SBP) Criteria Used to Determine Eligibility for Rescreening Age (yr) SBP (mm Hg)~ 106 11 t>108 12 I>110 13 />112 14 />114 15 I>114 />16 Not eligible for study aRepresents approximatelythe 70th percentileof age-specificdistribution.
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Table 4
P r e r a n d o m i z a t i o n Clinic Visit Schedule a n d Data Collection a Weeks
0 Clinic visit 1
2 Clinic visit 2
Information presentation Questions and answers
Physical exam Ht and Wt
Sign consent form Appointment for CV-2
BP 3-day food record 24-hour urine U/A CBC Blood chemistry Participant medical history Family medical history Family social history Appointment for CV-3
4 Clinic visit 3
6 Clinic visit 4
BP Girth and skin-fold
BP Review capsule trial
Intervention interview
Randomization Parent BP Piers-Harris POMS ACQ
Exercise questionnaire Sleep questionnaire Food frequency questionnaire ECG Begin 2-week trial of capsules Appointment for CV-4
aBP = Blood Pressure; Ht & Wt = Height & Weight; 24-hour Urine = 24-hour collection for Na +, K *, Cl, creatinine, Ca + *, and Mg + +; U/A = Urinalysis; CBC = Complete blood count; ECG = Electrocardiogram; Blood chemistry = serum Na ÷, K ÷, Cl-, HC03, BUN, Creatinine, Ca ÷ ÷, P, Alk p'tase, LD, AST; POMS = Profile of Mood States Questionnaire; Piers-Harris = The Piers-Harris Children's Self-concept Scale; ACQ = ACQ Behavior Checklist for Ages 4-16.
excluded if t h e y fulfilled o n e or m o r e of the following exclusion criteria: (1) chronic illness, (2) father as the p r i m a r y single parent, a n d (3) family w i t h m o r e t h a n four children. A n a p p o i n t m e n t w a s m a d e for the r e m a i n i n g initially eligible children a n d their p a r e n t s to a t t e n d the first clinic visit. At this visit the objectives a n d protocol for the s t u d y w e r e discussed, p a r e n t s a n d children h a d an o p p o r t u n i t y to h a v e questions a b o u t the s t u d y a n s w e r e d a n d it w a s e m p h a s i z e d that selection for this trial w a s b a s e d o n l y o n a potential partici p a n t h a v i n g a b l o o d p r e s s u r e in the u p p e r p a r t of a n o r m a l b l o o d p r e s s u r e distribution a n d not on a diagnosis of h y p e r t e n s i o n . Written c o n s e n t w a s o b t a i n e d f r o m p a r e n t s a n d children a n d an a p p o i n t m e n t w a s m a d e for the second clinic visit. Children c h o o s i n g to a t t e n d the s e c o n d clinic visit w e r e instructed in c o m p l e t i n g a 3-day food record a n d 24h o u r urine collection. Clinic Visits 2, 3, and 4. The second, third, a n d fourth p r e r a n d o m i z a t i o n clinic visits w e r e s e p a r a t e d b y a p p r o x i m a t e l y 2 w e e k s a n d w e r e u s e d to collect baseline data a n d to pretest c o m p l i a n c e in potential participants (Table 4). R a n d o m i z a t i o n w a s carried o u t at the e n d of CV-4. Blood p r e s s u r e (right a r m seated) w a s m e a s u r e d twice at each visit, w i t h the a v e r a g e of the m e a s u r e m e n t s f r o m CV-4 u s e d as the "baseline" b l o o d p r e s s u r e levels for the study. Particular attention w a s given to activities that w e r e s c h e d u l e d to recur t h r o u g h o u t the 4 y e a r s of the trial. The 24-hour urine s a m p l e a n d 3 - d a y food record w e r e r e t u r n e d at CV-2. If the participant failed to r e t u r n either of these at CV-2, if the urine s a m p l e w a s 500 ml or lower, or if the f o o d record w a s incomplete, the child w a s g i v e n a second o p p o r t u n i t y to successfully c o m p l e t e
Sodium-Potassium BP Trial in Children: Design
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these tasks. A second failure with either of these resulted in ineligibility for the trial. At CV-3 each child was started on a 2-week trial of potassium chloride capsules, two capsules each morning and two capsules each afternoon, to determine willingness to be enrolled in the capsule-taking groups and offer an opportunity to identify any potential problems associated with the capsules. A telephone call was made to the child during this 2-week trial period to review the capsule-taking experience. At C V 4 the capsule taking experience was reviewed again and a capsule count was performed. Participants w h o had taken 75% or more of the assigned capsules, had successfully completed all tasks included in clinic visits 2-4, and had no other exclusion criteria (Table 5) were randomized into one of the four study groups, if they consented.
Long-Term Evaluation Clinic visits. Table 6 presents the data collection schedule for the treatment groups. Each participant, with the exception of the control group, is seen every 3 months throughout the study for measurement of blood pressure, height, and weight. At the 3-month and at each 6-month visit a 24-hour urine sample and routine urinalysis are obtained, and a 3-day food record is completed. At the 3-month and at each 12-month visit a blood sample is obtained for a CBC and serum sodium, potassium, and creatinine. An electrocardiogram is performed yearly, and an echocardiogram is obtained during the first and fourth years of the study. Selected questionnaires (food frequency, family history, social history, exercise, and sleep) are completed at the yearly visits: CV-8, CV-12, CV-16 and CV-20. In addition, the POMS, Piers-Harris, and the ACQ tests are given at CV-4 and repeated at CV-20 to assess the behavioral and psychologic impact on the participants of becoming aware they have high normal blood pressure and participating in the trial. The only postrandomi-
Table 5 Exclusion Criteria Prior to Randomization a. Systolic blood pressure 1>140 mm Hg and/or diastolic blood pressure I>90 mm Hg, as determined from the average of all right arm blood pressure measurements obtained in clinic visits CV-2, CV-3, and CV-4. b. Diastolic blood pressure of 100 mm Hg or greater at any visit. c. History of renal disease with significant hematuria or proteinuria, or serum creatinine greater than 1.5 mg/dl. d. Hypokalemia e. Chronic systemic illness f. Inability to complete entire 3-day food record or adequate 24-hour urine collection after two attempts. g. Potential difficulty adhering to low sodium diet, e.g., largest meal of day eaten away from home on a regular basis. h. Failure to comply with capsule taking (i.e.,
ABSTRACT: The Sodium-Potassium Blood Pressure Trial in Children (NaKS), is a clinical trial in a healthy, free living population of children and adolescents. It is designed to test the hypotheses that a reduction in dietary sodium and/or an increase in potassium intake will decrease the rate of rise in blood pressure during normal maturation in children and adolescents with high normal blood pressure. Screening was conducted in 19,452 students in grades 5-8 in Minneapolis and St. Paul between January 1986 and May 1987. After screening, 3,223 students were found to have blood pressures that fulfilled the initial eligibility criteria for the study, and of these, 643 (20.0%) attended the orientation meeting, i.e., the first clinic visit. A total of four clinic visits, designed to test the willingness and capability of the potential participants to comply with the study protocol were conducted prior to randomization. At the conclusion of the four prerandomization visits, 243 children (7.5% of the initially eligible children) agreed to be randomized to one of four trial groups: low-sodium diet; potassium supplement administration; placebo-treated control group; and a no-treatment control group (to test the effect of acclimatization on blood pressure measurements) that will not be seen after randomization until the 4-year termination of the study. The first participant was randomized into the study on June 17, 1986, and the last on December 29, 1987. The potassium and placebo capsules are administered double-masked. Participants will be examined and receive intervention instruction four times yearly for 4 years counted from the date of their randomization. All groups were comparable with regard to distribution of school district, sex, and race and with respect to baseline physical characteristics. Results from this study will provide information about the feasibility and effect of dietary intervention during childhood and adolescence on the prevention of essential hypertension. KEY WORDS: Clinical trial, hypertension, children, sodium, potassium
Address reprint requests to: OrlandoG6mez-Maffn, PhD, Departmentof Epidemiologyand Public Health (R669), University of Miami Schoolof Medicine, P.O. Box 016069, Miami, FL 33101. Received June 15, 1990; revisedJanuary 22, 1991.
408 0197-2456/91/$3.50
Controlled ClinicalTrials 12:408-423(1991) © ElsevierSciencePublishing Co., Inc. 1991 655 Avenueof the Americas, New York, New York10010
Sodium-Potassium BP Trial in Children: Design
409
INTRODUCTION Blood pressure increases at a steady rate in children through early adolescence [1]. This increase follows a "tracking" pattern, in which children at a specific percentile of blood pressure distribution tend to maintain that position as they grow older [2-4]. It has been suggested that children tracking at the upper deciles of blood pressure distribution are at increased risk to develop essential hypertension as adults, and recent data support this conclusion [5]. With the incorporation of blood pressure measurement into the pediatric physical examination and availability of accurate blood pressure distribution curves from a number of epidemiologic surveys [1], it has become clear that mild elevations of blood pressure may be more common than previously recognized in children. Thus, the dual issues of (1) effectiveness of introducing strategies during childhood and adolescence to prevent essential hypertension and (2) the most appropriate approach to children with borderline or mild hypertension have become highly relevant to pediatric health care delivery, and there is a need to establish whether nonpharmacologic antihypertensive treatment is feasible, effective, and safe in these age groups. This article presents the rationale, study plan, and recruitment results for a randomized controlled trial designed to test the effects of dietary sodium restriction or oral potassium supplementation on the rate of rise of blood pressure during late childhood and adolescence. In particular, it describes the recruitment of a cohort of junior high school-aged children and their families subjected to a rigorous prerandomization protocol. Modification of dietary sodium and potassium is a potential alternative to pharmacologic treatment for prevention and control of hypertension. The direct relationship between sodium and blood pressure was established by the early work of Dahl and colleagues in animals [6] and humans [7]. Evidence from epidemiologic studies supports the contension that sodium intake influences blood pressure levels within a population [8]. On the one extreme are isolated, unacculturated groups that subsist on low sodium diets and do not experience either an increase in blood pressure with age or the occurrence of hypertensive disease [9]; in contrast, in countries such as the United States where more than 20% of the adult population is hypertensive [10], sodium intake is far in excess of the amount required to satisfy nutritional needs [11,12]. Sodium sensitivity can be documented in some adults and children with hypertension [13-15], as well as in a segment of the normotensive population [16]. It has been shown that dietary sodium restriction causes sigrlificant reductions in blood pressure in adults with mild to moderate diastolic hypertension [17], that the antihypertensive response is related to the degree of sodium restriction [18], that the need for antihypertensive drugs can be reduced by sodium restriction in individuals being treated for hypertension [19], and that more modest reductions in blood pressure occur in normotensives placed on sodium-restricted or reduced diets [20,21]. However, the outcome following sodium restriction is not uniform, and other studies have not been able to show similar changes in blood pressure [22-25]. The antihypertensive effect of potassium has been known for approximately 50 years but has been overshadowed by interest in the relationship between sodium and blood pressure [26]. Potassium supplementation is known
410
o. G6mez-Maffn et al. to induce natriuresis, decrease plasma renin activity, inhibit adrenergic nervous system activity, and cause direct vasodffatation of peripheral blood vessels. Epidemiologic studies have shown an inverse relationship between both blood pressure and stroke and the intake of potassium [27,28]. Clinical experience with adequate potassium treatment is limited. Short-term trials in adults have shown only modest success in reducing blood pressure [24,29]. Patterns of dietary sodium and potassium preference are established during infancy, and the intake of sodium by children approaches that of adults by the end of the first year of life [30]. Because sodium intake by children is far in excess of daffy requirements, reduction in sodium intake or an increase in the intake of potassium may have a substantial impact on blood pressure in this age group. A positive outcome from this clinical trial could have implications for future research on the development and utility of early intervention in essential hypertension.
STUDY DESIGN Objectives The primary objective of The Sodium-Potassium Blood Pressure Trial in Children (NaKS) is to test the hypotheses that a reduction in dietary sodium and/or an increase in potassium intake decreases the rate of rise of blood pressure during normal maturation in children and adolescents with high normal blood pressure. This trial will establish the feasibility of sodium reduction or potassium supplementation and their effect on blood pressure in this age group, and it will develop a database for evaluation of the long-term effect of sodium/potassium intervention on the natural history of blood pressure during the adolescent-adult transition period. At the conclusion of four clinic visits conducted prior to randomization, participants were randomly assigned in the ratio of 2:2:2:1 to one of the following groups: 1. Low Sodium Diet Group: Dietary sodium reduction to 70 mEq daffy sodium intake. 2. Potassium Chloride Group: Daffy potassium supplementation of I mEq/kg body weight (maximum 80 mEq/day) with capsules containing potassium chloride. 3. Placebo-Treated Group: Daffy intake of placebo capsules. 4. Nontreated Control Group: Nonintervention group. The nontreated control group was included not for comparison of treatment effect, but only to compare with the placebo group the effect on blood pressure measurement of "acclimatization" from regular clinic visits. The first participant was randomized into the study on June 17, 1986, and the last on December 29, 1987.
Study Groups Low sodium diet group. This group is not administered any capsules. Participants in the group are instructed to perform a gradual reduction of dietary
Sodium-Potassium BP Trial in Children: Design
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sodium to a level of 1,600 mg (70 mEq/day/family member), according to the contact schedule outlined in Table 1. At each of the five group sessions, families are separated into children and parent groups for an educational session and then reunited for a low-sodium refreshment period and discussion. This strategy has been shown to be superior for achieving compliance in trials in children [31]. In addition, two sessions, where children and parents meet together, are held for each family, and three telephone contacts are made to monitor progress, problem solve, and to offer support. At each 3monthly clinic visit during the 4-year maintenance phase of the trial, participants meet with a study interventionist for ongoing education, reinforcement, and support. To specifically determine dietary sodium intake, parents and children are instructed in record keeping using 3-day food records and sodium point tally sheets. The amount of sodium (mEq) consumed on each of 3 days is averaged, and this value is used for analysis. Compliance is assessed by analysis of the 3-day food records and electrolyte measurements in 24-hour urine samples.
Capsule groups. The capsule treatment is a double-masked design, with capsule content known only to the Data and Safety Monitoring Committee. Potassium Supplementation Group. The participants in this treatment group remain on their normal diets without any dietary sodium modification. In addition, they receive potassium supplementation calculated to increase their potassium intake above usual dietary levels by I mEq/kg body weight per 24 hours (maximum of 80 mEq per 24 hours). Potassium chloride intake is adjusted during the trial according to changes in body weight associated with growth. Potassium chloride is administered in capsules (Micro-K, 8 mEq or 600 mg KC1 per capsule, kindly supplied by Wyeth-Ayerst) containing film-coated microencapsulated KC1 crystals. The daily potassium requirement is divided into two equal amounts administered morning and evening with meals. At each 3-monthly visit, children in this group meet with a study interventionist. Compliance in the KC1 group is assessed by measurement of electrolytes in 24-hour urine samples and by pill counts at each visit. Placebo-Treated Group. Participants in this group are treated in an identical fashion to the potassium supplementation group. Table 1 Initial Contact Schedule for the Dietary Sodium Group Weeka Contact Content 1 Mail/phone Notification of group session and follow-up reminder call Low sodium seasonings 2 Group Daily sodium menu planning 3 Group Nutrition, label reading, and low-sodium lunches 4 Group 5 Individual Progress check 6 Phone Follow up on progress Eating out 7 Group Snack preparation workshop 9 Group 11 Phone Progress check Review and progress check 12 Individual "Weeks after randomization.
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Nontreated control group. After randomization, participants in this group are not seen by the staff for the 4-year duration of the trial. Their addresses and telephone numbers are updated yearly in the study files, and they are contacted by mail at birthdays and holidays. At the end of the study this group will be seen for a complete health status assessment.
Sample Size The design of this trial is a repeated-measures design with 17 measurements of blood pressure, height, and weight (every 3 months) and 9 measurements of sodium intake, and urinary sodium, potassium, chloride, calcium, magnesium, and creatinine (every 6 months). The main null hypothesis, i.e., there is no difference between treatment groups with respect to the rate of rise of blood pressure, will be tested by comparing the linear trends resulting from the orthogonal decomposition of the "group × time" interaction in a repeatedmeasures analysis of variance. Sample sizes needed to test the hypothesis with adequate power were initially calculated by considering the three treatment groups (Low Sodium Diet, Potassium Supplementation, and Placebo) and using longitudinal data from the Minneapolis Children's Blood Pressure Study [2,32] to estimate the standard error of the linear contrast. Since the three possible pairwise comparisons of linear contrasts are of interest, the sample size calculations were performed using one third of the nominal levels. Table 2 shows that, for example, a difference in rate of increase of blood pressure of 0.75 mm Hg/yr (i.e., difference of 3.0 mm Hg in blood pressure levels after 4 years of intervention) can be detected with 85% power at a nominal ot level of 0.05 with 61 participants in each of the three treatment groups.
Duration of the Trial Participants in this trial will be.evaluated over 4 years, counted from their date of randomization. Trials in adults using sodium reduction and/or potassium supplementation have been conducted over much shorter periods of
Table 2 Number of Subjects Required in Each of Three Treatment Groups to Detect Specified Pairwise Differences in Rate of Increase of Systolic Blood Pressure (mm Hg per year) at Given Power and a Levels Pairwise Differences in Rate of Increase of SBP (ram Hg/yr) c~ Levela 0.625 0.750 0.875 1.000 1.125 1.250 Power 0.80 0.01 106 73 54 41 32 26 0.05 79 55 40 31 24 20 0.85 0.01 118 81 60 46 36 29 0.05 89 61 45 35 27 22 0.90 0.01 132 91 67 51 41 33 0.05 102 70 52 40 31 25 0.95 0.01 156 108 80 61 48 39 0.05 123 85 63 48 38 31 ~Toadjust for multiplepairwise comparisons,the sample size calculationswere performedusing one third of these nominala levels.
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time, because the outcome of those trials, i.e., degree of antihypertensive response in individuals with significant hypertension, usually' can be determined within weeks or months. In contrast, evaluation of the effect of nonpharmacologic treatment on the gradual increase in blood pressure, characteristic of the first and second decades of life [2], was estimated to require a greater longitudinal commitment. In addition, the effectiveness of this intervention is dependent, in part, on allowing sufficient time to establish the behavioral changes required by each of the treatment groups. Therefore, the 4-year observation period was deemed necessary to assess the major hypotheses.
Recruitment of Participants Blood pressure measurement and eligibility. Participants for this trial were recruited from 5th, 6th, 7th, and 8th grade students in the Minneapolis and St. Paul public schools. During the period from January 1986 to May 1987, screening of blood pressure was conducted in schools during regular school days. Children had their blood pressure measured twice on the right arm and in the seated position by trained personnel, using a standard clinical sphygmomanometer and following a standardized protocol [32]. All children whose systolic blood pressure (mean of two measurements) equalled or exceeded the 70th percentile of age-specific distribution (Table 3) had their blood pressure measured on a second occasion (rescreening) under identical circumstances. All white, black, Hispanic, white/black, white/Hispanic, and black/Hispanic children whose blood pressure at rescreening was above 109 m m Hg for boys and 108 m m Hg for girls (i.e., approximately the upper 15% of all children screened) were invited to participate in the trial. Recruitment clinic visits. The children were seen at four separate visits prior to randomization. Each of these visits was held in the study clinic. The schedule of these clinic visits and the list of data collected at each of them are given in Table 4. Orientation Meeting (Clinic Visit 1, CV-1). All children eligible after rescreening received a letter inviting them to participate in the trial. The letter was followed, within 10 days, by a telephone call during which children were Table 3 Systolic Blood Pressure (SBP) Criteria Used to Determine Eligibility for Rescreening Age (yr) SBP (mm Hg)~ 106 11 t>108 12 I>110 13 />112 14 />114 15 I>114 />16 Not eligible for study aRepresents approximatelythe 70th percentileof age-specificdistribution.
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Table 4
P r e r a n d o m i z a t i o n Clinic Visit Schedule a n d Data Collection a Weeks
0 Clinic visit 1
2 Clinic visit 2
Information presentation Questions and answers
Physical exam Ht and Wt
Sign consent form Appointment for CV-2
BP 3-day food record 24-hour urine U/A CBC Blood chemistry Participant medical history Family medical history Family social history Appointment for CV-3
4 Clinic visit 3
6 Clinic visit 4
BP Girth and skin-fold
BP Review capsule trial
Intervention interview
Randomization Parent BP Piers-Harris POMS ACQ
Exercise questionnaire Sleep questionnaire Food frequency questionnaire ECG Begin 2-week trial of capsules Appointment for CV-4
aBP = Blood Pressure; Ht & Wt = Height & Weight; 24-hour Urine = 24-hour collection for Na +, K *, Cl, creatinine, Ca + *, and Mg + +; U/A = Urinalysis; CBC = Complete blood count; ECG = Electrocardiogram; Blood chemistry = serum Na ÷, K ÷, Cl-, HC03, BUN, Creatinine, Ca ÷ ÷, P, Alk p'tase, LD, AST; POMS = Profile of Mood States Questionnaire; Piers-Harris = The Piers-Harris Children's Self-concept Scale; ACQ = ACQ Behavior Checklist for Ages 4-16.
excluded if t h e y fulfilled o n e or m o r e of the following exclusion criteria: (1) chronic illness, (2) father as the p r i m a r y single parent, a n d (3) family w i t h m o r e t h a n four children. A n a p p o i n t m e n t w a s m a d e for the r e m a i n i n g initially eligible children a n d their p a r e n t s to a t t e n d the first clinic visit. At this visit the objectives a n d protocol for the s t u d y w e r e discussed, p a r e n t s a n d children h a d an o p p o r t u n i t y to h a v e questions a b o u t the s t u d y a n s w e r e d a n d it w a s e m p h a s i z e d that selection for this trial w a s b a s e d o n l y o n a potential partici p a n t h a v i n g a b l o o d p r e s s u r e in the u p p e r p a r t of a n o r m a l b l o o d p r e s s u r e distribution a n d not on a diagnosis of h y p e r t e n s i o n . Written c o n s e n t w a s o b t a i n e d f r o m p a r e n t s a n d children a n d an a p p o i n t m e n t w a s m a d e for the second clinic visit. Children c h o o s i n g to a t t e n d the s e c o n d clinic visit w e r e instructed in c o m p l e t i n g a 3-day food record a n d 24h o u r urine collection. Clinic Visits 2, 3, and 4. The second, third, a n d fourth p r e r a n d o m i z a t i o n clinic visits w e r e s e p a r a t e d b y a p p r o x i m a t e l y 2 w e e k s a n d w e r e u s e d to collect baseline data a n d to pretest c o m p l i a n c e in potential participants (Table 4). R a n d o m i z a t i o n w a s carried o u t at the e n d of CV-4. Blood p r e s s u r e (right a r m seated) w a s m e a s u r e d twice at each visit, w i t h the a v e r a g e of the m e a s u r e m e n t s f r o m CV-4 u s e d as the "baseline" b l o o d p r e s s u r e levels for the study. Particular attention w a s given to activities that w e r e s c h e d u l e d to recur t h r o u g h o u t the 4 y e a r s of the trial. The 24-hour urine s a m p l e a n d 3 - d a y food record w e r e r e t u r n e d at CV-2. If the participant failed to r e t u r n either of these at CV-2, if the urine s a m p l e w a s 500 ml or lower, or if the f o o d record w a s incomplete, the child w a s g i v e n a second o p p o r t u n i t y to successfully c o m p l e t e
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these tasks. A second failure with either of these resulted in ineligibility for the trial. At CV-3 each child was started on a 2-week trial of potassium chloride capsules, two capsules each morning and two capsules each afternoon, to determine willingness to be enrolled in the capsule-taking groups and offer an opportunity to identify any potential problems associated with the capsules. A telephone call was made to the child during this 2-week trial period to review the capsule-taking experience. At C V 4 the capsule taking experience was reviewed again and a capsule count was performed. Participants w h o had taken 75% or more of the assigned capsules, had successfully completed all tasks included in clinic visits 2-4, and had no other exclusion criteria (Table 5) were randomized into one of the four study groups, if they consented.
Long-Term Evaluation Clinic visits. Table 6 presents the data collection schedule for the treatment groups. Each participant, with the exception of the control group, is seen every 3 months throughout the study for measurement of blood pressure, height, and weight. At the 3-month and at each 6-month visit a 24-hour urine sample and routine urinalysis are obtained, and a 3-day food record is completed. At the 3-month and at each 12-month visit a blood sample is obtained for a CBC and serum sodium, potassium, and creatinine. An electrocardiogram is performed yearly, and an echocardiogram is obtained during the first and fourth years of the study. Selected questionnaires (food frequency, family history, social history, exercise, and sleep) are completed at the yearly visits: CV-8, CV-12, CV-16 and CV-20. In addition, the POMS, Piers-Harris, and the ACQ tests are given at CV-4 and repeated at CV-20 to assess the behavioral and psychologic impact on the participants of becoming aware they have high normal blood pressure and participating in the trial. The only postrandomi-
Table 5 Exclusion Criteria Prior to Randomization a. Systolic blood pressure 1>140 mm Hg and/or diastolic blood pressure I>90 mm Hg, as determined from the average of all right arm blood pressure measurements obtained in clinic visits CV-2, CV-3, and CV-4. b. Diastolic blood pressure of 100 mm Hg or greater at any visit. c. History of renal disease with significant hematuria or proteinuria, or serum creatinine greater than 1.5 mg/dl. d. Hypokalemia e. Chronic systemic illness f. Inability to complete entire 3-day food record or adequate 24-hour urine collection after two attempts. g. Potential difficulty adhering to low sodium diet, e.g., largest meal of day eaten away from home on a regular basis. h. Failure to comply with capsule taking (i.e.,
