EAL

Disorders of Lipid Metabolism and Micronutrients

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The researchers studied the relationship of salt sensitivity to age and changes in blood pressure over time. The purpose was to determine if salt sensitivity in hypertension is a natural process of aging or whether other factors may be involved. This study had three separate components that were being investigated: Reproducibility, relation to age and changes in blood pressure over time.

Inclusion Criteria:

Included were subjects who stopped taking antihypertensive medication(s) for at least two weeks before the study.

Exclusion Criteria:

Individuals were excluded if they:

Were on estrogen therapy
Were taking nonsteroidal anti-inflammatory agents
Were on medication known to affect salt and water hemodynamics
Had a diastolic blood pressure of 115mm Hg or greater
Had a history of myocardial infarction (MI) or stroke in the preceding six months
Had congestive heart failure
Had a serum creatinine of 2.0mg per dL or higher
Had other significant medical illnesses.

Description of Study Protocol:

Recruitment

The Clinical Research Center at Indiana University Medical Center.

Design

Diagnostic study.

Intervention

Sodium loading (intravenous sodium) and sodium per volume depletion (10mmol per day of dietary sodium and administration of furosemide), using a modified Grim test.

Statistical Analysis

Data were analyzed by paired and unpaired T-tests, X² comparisons, repeated measures analysis analysis of variance and covariance, and linear regressions analysis
Differences were significant at P<0.05
Decreased mean arterial pressure of 10mm Hg or greater was classified as sodium-sensitive. A change in blood pressure of 5mm Hg or less was designated as salt-responsive. A decrease in mean arterial pressure of 6.0 to 9.0mm Hg was considered indeterminate for classification purposes.
To assess changes in blood pressure over time, blood pressure changes between the two periods were divided by the number of years to provide the rate of blood pressure change.

Data Collection Summary:

Timing of Measurements

Increased extracellular fluid volume and sodium balance was achieved with intravenous infusion of two liters of normal sodium chloride (0.9%) at a rate of 500ml per hour between 8:00 A.M. and noon after one day in the Clinical Research Center
On the next day, sodium and volume depletion were induced by 10mmol per day dietary sodium intake and furosemide, 40mg by mouth at 10:00 A.M., 2:00 P.M. and 6:00 P.M. Blood samples and blood pressure were obtained at 6:00 A.M. (upon waking) and 8:00 A.M. (after two hours of ambulation) on each of three days. Blood pressure was assessed by mean arterial pressure after the saline infusion and compared with the morning after sodium and volume depletion.

Dependent Variables

Variable One: Blood pressure changes with age
Variable Two: Change in blood pressure with time.

Independent Variables

Sodium infusion
Sodium and volume depletion.

Description of Actual Data Sample:

Initial N

28 subjects in Study A, the reproducibility phase
660 subjects in Study B, which focused on the relationship of age (430 normotensive and 230 hypertensive)
31 subjects in Study C, which assessed the change in blood pressure with time.

Attrition (final N)

Same as initial numbers.

Location

Hypertension Research Center at the Indiana University School of Medicine in Indianapolis, Indiana.

Summary of Results:

Study A: Reproducibility

A reproducible response was noted (R=0.56, P<0.002)
Four subjects changed categories at the second measurement, one from salt-resistant to salt-sensitive and three from salt-sensitive to salt-resistant
Six subjects were reclassified into the indeterminate category after three were initially classified as salt-sensitive and the other three were salt-resistant.

Study B: Relation to Age

A significant inverse correlation was noted between blood pressure response used to classify sodium response and subject age (R=-0.38, P<0.001)
When the normotensive and hypertensive groups were observed separately, the above relation remained (normotensive, R=-0.19, P<0.01; hypertensive, R=-0.31, P<0.001)
The researchers noted a significant increase in sodium sensitivity among hypertensives as compared to normotensive subjects aged 31 to 40, 41 to 50, and 51 to 60 (P<0.01). These changes were not seen in subjects who were younger than age 31 or older than age 60.
Normotensive subjects: In the below-30 age group, 65% were salt-resistant and 35% salt-sensitive or indeterminate. In the 50-and-older age group, 77% were salt-sensitive or indeterminate and 23% were salt-resistant.
Hypertensive subjects: In the younger-than-30 age group, 50% were salt-resistant and 50% were salt-sensitive. In the 50 and older group, 85% were salt-sensitive or indeterminate and 15% were salt-resistant.
The differences between the normotensive and hypertensive subjects were significant when measured by X² test (normotensive X²=23.6, P<0.001; hypertensive X²=10.4, P<0.001).

Study C: Change in Blood Pressure with Time

At the initial measurement, 15 subjects were salt-resistant and 16 were salt-sensitive. These subjects had blood pressure measurements 10 or more years after the initial study.
Salt-resistant subjects were significantly younger (P<0.02) and had significantly lower systolic and diastolic blood pressure measurements than the sodium-sensitive subjects
Systolic blood pressure: Salt-resistant subjects had a mean decrease of -0.32±0.15mm Hg per year. Salt-sensitive subjects had a mean increase of 1.42±0.39mm Hg per year (P<0.001).
Mean arterial blood pressure: Between the two measurements, the salt-resistant group had an average change of -0.2±1.8mm Hg. The change in the salt-sensitive group was 10.2±3.6mm Hg (P<0.02).
Diastolic blood pressure: Salt-resistant subjects had a change of 0.16±0.23mm Hg per year. Salt-sensitive subjects had a change of 0.66±0.33mm Hg per year (P=0.23).
When the analysis of covariance was conducted and corrected for age differences between the groups, all three measures of blood pressure change remained significant (systolic, P<0.001; diastolic, P<0.01; mean arterial, P<0.001)
No significant differences were observed in blood pressure changes between normotensive and hypertensive subjects.

Study C: Change in Blood Pressure Over Time (More Than 10 Years)

Subject Observations	Salt-Resistant	Salt-Sensitive
N	15	16
Age (year)
One	29±3*	40±3
Two	40±3*	52±3
Systolic pressure (mm Hg)
One	113±3*	126±5
Two	110±11^†	142±4
Diastolic pressure (mm Hg)
One	70±3*	80±3
Two	72±2^†	88±3
Systolic (mm Hg per year)	-0.32±0.15^†	1.42±0.39
Diastolic (mm Hg per year)	0.16±0.23	0.66±0.33

Values are mean±SD.
N, number of subjects.
Analysis of variance correcting for age: Systolic^†, diastolic^‡.
*P<0.05,^†P<0.001, ^‡P<0.01.

Author Conclusion:

The assessment of salt sensitivity and salt resistance used in this study is reproducible. The presence of salt sensitivity, as defined by this study's approach, predicts a greater subsequent increase in blood pressure over time than does salt resistance.

Funding Source:

Government:

U. S Public Health Service (partial funding)

Reviewer Comments:

These results may be important for future treatment and possibly prevention of salt-sensitive hypertension.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	???
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	???
	4.	Was method of handling withdrawals described?	Yes
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	N/A
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
	5.	Was blinding used to prevent introduction of bias?	N/A
5.	Was blinding used to prevent introduction of bias?		N/A
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
	6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
	7.	Were outcomes clearly defined and the measurements valid and reliable?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
	8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
	9.	Are conclusions supported by results with biases and limitations taken into consideration?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
	10.	Is bias due to study's funding or sponsorship unlikely?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes