Heart Failure

HF: Fluid and Sodium Restriction (2006)


Alvelos, M, Ferreira, A, Bettencourt P, et al. The effect of dietary sodium restriction on neurohumoral activity and renal dopaminergic response in patients with heart failure. Eur J Heart Failure. 2004; 6: 593-599.

Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To evaluate the effect of dietary sodium restriction on neurohumoral activation and renal dopaminergic system response in mild-to-moderate compensated heart failure (HF). 
Inclusion Criteria:
  • Mild-to-moderate HF
  • Left ventricular ejection fraction lower than 40%
  • No exacerbations or therapeutic changes in the previous two months.
Exclusion Criteria:
  • Concomitant significant valve disease
  • Renal or hepatic failure
  • Diabetes mellitus
  • Pulmonary disease.
Description of Study Protocol:
  • Recruitment: Not described
  • Design: RCT
  • Intervention: Controlled low-sodium diet (100mmol Na+ per day).


Statistical Analysis

  • Mann-Whitney U-test was used to evaluate differences in numerical variables between the two groups
  • Wilcoxon's signed-ranks test was used to test for differences between measurements performed at baseline and after the 15-day diet period
  • For comparisons of categorical variables, we used the likelihood ratio, Chi-square or Fisher's exact test, when appropriate
  • Data are expressed as mean ±SEM
  • P<0.05 is considered statistically significant
  • Statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS).


Data Collection Summary:

Timing of Measurements

Baseline and after 15 days.

Dependent Variables

  • Venous blood samples of L-DOPA, dopamine, DOPAC, adrenaline, noradrenaline, aldosterone, BNP, sodium and creatinine were obtained from an antecubital vein after a 20-minute rest in the supine position between 8:00 a.m. and 10:00 a.m. after an overnight fast. The blood was immediately chilled in plastic tubes with heparin (catecholamines) and K3EDTA (aldosterone and BNP), centrifuged (at 4.500 RPM for 15 minutes at 0oC) and stored at -80oC until assayed.
  • 24-hour urine collections were obtained for L-DOPA, dopamine, DOPAC, homovanillic acid, noradrenaline, sodium and creatinine. The collections were collected in plastic containers with 15ml of six m HCL to prevent spontaneous decomposition of monoamines and amine metabolites. Urine samples were stored in plastic tubes at -80oC until assay. Quantification of catecholamines and its metabolites in urine (L-DOPA, dopamine, DOPAC, homovanillic acid and noradrenaline) and plasma samples (L-DOPA, dopamine, DOPAC, homovanillic acid and noradrenaline) was performed by high-performance liquid chromatography with electrochemical detection. Dihydroxybenzylamine was used as an international standard and the interassay coefficient of variation was less than 5%. The lower limit of detection of L-DOPA, dopamine, DOPAC, homovanillic acid, adrenaline and noradrenaline ranged from 350fmol to 1,000fmol. The assay of sodium in urine and plasma samples was performed by indirect potentiometry, using the autoanalyzer Beckman Synchron CX3. The assay of creatinine in urine and plasma samples was performed using the kinetic technique with Jaffe reaction, also using the satoanalyzer Beckman Synchron CX3 and creatinine clearance was calculated according to the formula [(UCr/PCr)xUVol]/1440, where UCr is urinary creatinine, PCR is plasma creatinine and UVol is urine volume. Frational excretion of sodium was calculated using the equation [UNa xPCr)/PNa xUCr]x100, where UNa is urinary sodium, PNa is plasma sodium, UCr if urinary creatinine and PCr is plasma creatinine. 
  • M-mode and two-dimensional echocardiograms were performed in all patients using the same echocardiography unit (Hewlett Packard Sonos 5500). Left ventricular systolic function was assessed by measurement of left ventricle ejection fraction using the biplane disc summation method or the Bullet single and biplane ellipse method.   

Independent Variables

Controlled 100mmol Na+ diet; no further description.

Description of Actual Data Sample:
  • Initial N: 24 (17 males, seven females)
  • Attrition (final N): Not described
  • Age: 68.2±3.7 years in control and 71.5±2.7 years in low-sodium
  • Ethnicity: Not described.


  • There were no significant differences in body surface area, ischemic etiology, atrial fibrillation, NYHA class, left ventricle ejection fraction or medications
  • Most of the subjects were on angiotensin-converting enzymen inhibitiors and the remainder on angiotensin II antagonists
  • None were on spironolactone, non-steroidal anti-inflammatory drugs or other drugs known to affect sodium handling or renal production of dopamine
  • Both groups were similar in usage of diuretics, beta-blockers and digoxin. 


Hospital S. Joao, Porto, Portugal.

Summary of Results:


Treatment Group, Baseline
(Measures and Confidence Intervals)

Treatment Group, After

Statistical Significance of Group Difference

Control Group, Baseline
(Measures and Confidence Intervals)

Control Group, After

Statistical Significance of Group Difference

Urine Volume (ml/day-1)







Urine creatinine (g/day-1)







Urine Sodium (mEq/day-1)







Creatinine Clearance (ml/min-1 1.73m-2)







Fractional Excretion of Sodium (percentage)







L-DOPA (pmol/ml-1)







Dopamine (pmol/ml-1)







 DOPAC (pmol/ml-1)







Body Weight (kg)







Other Findings

  • NYHA functional class was not affected by sodium restriction
  • The renal delivery of L-DOPA and the urinary excretion of L-DOPA were significantly reduced by the low-sodium diet, while dopamine and its metabolites were not affected
  • Urinary dopamine-to-L-DOPA ratio and urinary dopamine-to-renal delivery of L-DOPA ratio were significantly increased by the low-sodium diet
  • Plasma L-DOPA decreased, while plasma dopamine increased on the the low-sodium diet
  • Plasma aldosterone rose slightly and BNP significantly decreased on the low-sodium diet
  • There was a decrease in mean blood pressure without clinical repercussions on the low-sodium diet
  • None of these occurred in the controls.
Author Conclusion:

Salt restriction in patients with mild-to-moderate stable HF under diuretic therapy may induce volume depletion and neurohumoral activation. However, increases in the renal rate of L-DOPA utilization during sodium restriction may relate to activation of counter-regulatory mechanism.

Funding Source:
University/Hospital: Piso 9, Hospital S. Joao, University of Porto Medical, Hospital S. Joao
Reviewer Comments:
  • There is no decription of the low-sodium diet other than the discussion states that it was a controlled intake.
  • The text states that there was a significant change in body weight from baseline on the low-sodium diet (P≤0.02) and not on the control diet (P≤0.07). However, in the table listing the variations in study variables, the difference for body weight between controls and the low-sodium group had a P-value of 0.36.
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
  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
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? 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
  2.2. Were criteria applied equally to all study groups? 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
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) No
  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
  3.4. 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
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  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%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? 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
5. Was blinding used to prevent introduction of bias? No
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? No
  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.) No
  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
  5.5. 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
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? No
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  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
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) 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? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
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
  7.2. 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
  7.4. 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
  7.6. Were other factors accounted for (measured) that could affect outcomes? 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
  8.1. 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
  8.3. 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
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  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
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? No
  10.1. Were sources of funding and investigators' affiliations described? No
  10.2. Was the study free from apparent conflict of interest? ???