Heart Failure

HF: Fluid and Sodium Restriction (2006)

Citation:

Damgaard M, Norsk P et al. Hemodynamic and neuroendocrine responses to changes in sodium intake in compensated heart failure, Am J Physiol Regul Integr Comp Physiol. 2006, 290: R1294-R1301.

 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:

To investigate whether the hemodynamic and neuroendocrine responses to variations in sodium intake would be different between medically-treated compensated HF patients and healthy controls after one week of high and one week of low sodium intake.

Inclusion Criteria:
  • Compensated HF with left ventricular ejection fraction below 40% in sinus rhythm
  • Normal glucose and creatinine levels
  • Normal spirometry
  • Control subjects healthy by medical history and routine clinical evaluation including spirometry and echocardiography.
Exclusion Criteria:

HF patients: Symptomatic ischemic disease documented by an exercise test, recent history of acute myocardial infarction, angina pectoris or cardiac decompensation (less than two months).

 

 

Description of Study Protocol:

Recruitment

Not described.

Design

  • The study was two consecutive seven-day periods in which the subjects were on a 70-mmol-per-day, then a 250-mmol-per-day sodium isocaloric diet or vice versa, in balanced randomized manner
  • Water intake was not controlled
  • 24-hour urines were collected for renal sodium excretion during the final 10 days
  • On the final day of each dietary period, the hemodynamic and neuroendocrine measurements were performed after the subjects had voided, were weighed and drank 200ml of water while resting in an armchair for 30 minutes. 

Blinding Used

The echocardiograms were analyzed in a blinded fashion.

Intervention

Two consecutive seven-day periods in which the subjects were either on a 70-mmol-per-day or 250-mmol-per-day sodium isocaloric diet in a balanced randomized manner. Water intake was not controlled. No further description of the diet control was described. The author was contacted and the following information was provided:

  • "A specific diet with a sodium content of 70mmol per day was composed by the investigators (incuding a dietitian). All meals were delivered (daily) to the patients at their homes. The meals were packed separately (breakfast, lunch, dinner) and the participants were instructed in the cooking procedure (hot meals). All particpants were given a 24-hours possibility to contact the study group in case of dietary or health questions."
  • "In the high sodium periods, all subjects were given 180mmol additional sodium per day. This was divided into small parts and eaten in conjunction with the meals. All participants were encouraged to continue their normal daily activities throughout the study."

Statistical Analysis

  • Data are presented as means ±SE. Angiotensin II (ANG II) and norepinephrine (NE) were normally distributed after log transformation and are therefore presented as geometric means (95% confidence intervals). Epinephrine (Epi) and natriuretic peptide (pro-BNP) could not be transformed to normality and are therefore presented as medians (interquartile range).
  • The effect of sodium on hemodynamics and neuroendocrine variables within the groups was evaluated using a paired T-test or Wilcoxon signed-rank test, as appropriate. To evaluate differences between the groups, we applied an unpaired T-test or the Mann-Whitney U-test. 
  • A one-way ANOVA for repeated measures, followed by post-hoc T-tests (Bonferroni correction), was performed with the groups used to detect an effect of time on renal sodium excretion and to evaluate the effect of exercise intensity on the sodium-induced changes in hemodynamics variables. In all statistical analyses, the significance level of 0.05 was chosen. The statistical analyses were performed using Sigmastat for Windows (version 2.03; SPSS).
Data Collection Summary:

Timing of Measurements

On the final day of each dietary period, after taking habitual morning medication (HF patients only) and after voiding, being weighed and instrumented (not described), the subjects drank 200ml of water while resting in an armchair for 30 minutes before the hemodynamic and neuroendocrine measurements were performed at seated rest, supine rest and during bicycle exercise.

Dependent Variables

  • Cardiac output was derived from three measurements of pulmonary capillary blood flow by inert gas rebreathing. A closed system containing a rebreathing gas mixture (0.5% N20, 0.1% SF6 and 28% O2 in N2) connected to an infrared photoacoustic gas analyzer was used (Innovision, Odense, Denmark). Rebreathings were performed for 25 seconds with a gas volume of 30% of the subject's vital capacity and a breathing rate of 20 breaths per minute.
  • Pulmonary blood flow was determined from the gas concentrtion traces.
  • Heart rate was obtained from ECG recordings
  • Arterial pressures were measured by sphygmomanometry between the rebreathings. All measurements were preformed with the brachial cuff at the level of the fourth intercostal space, while the patient was seated and at the level of the mid-axillary line while the patient was supine. 
  • Cardiac index (CI), stroke volume index (SVI), pulse pressure (PP), mean arterial pressure (MAP) and total peripheral resistance (TPR) were calculated using conventional formulas
  • Left atrial diameter was measured by echocardiography, using M-mode recordings obtained from the parasternal long-axis view. Printouts of the recordings were analyzed by the same investigator in a blinded fashion. 
  • Plasma volume (PV) was determined after one hour in the seated and supine positions by using human serum albumin labeled with radioactive iodine. After an initial blood draw, 200kBq of radioactive iodine were injected through a peripheral cubital venous catheter. From the opposite venous catheter, blood samples were collected at 10, 20 and 30 minutes after injection and PV was calculated from the radioactivity of the samples. All subjects received a thyroid-blocking dose of 400mg of potassium iodide two hours before the injections. The radiation exposure of the entire study was 0.24mSv. 
  • Blood samples were drawn from patients after one hour in each position and immediately centrifuged at 3,700rpm for 10 minutes and transfered to a freezer. Plasma concentrations of norepinephrine (NE) and epinephrine (Epi) were measured using radioenzymatic assay, whereas angiotensin II (ANG II) and pro-B-type natriuretic peptide (pro-BNP) were measured using radioimmunoassays. 
  • Hematocrit was determined on fresh blood samples by centrifugation of microhematocrit tubes for five minutes at 12,600g. Plasma concentration of sodium, potassium and albumin, blood urea nitrogen (BUN), hemoglobin, urine osmolality and sodium concentrtion were analyzed using conventional methods. 
  • After a three-hour break, an incremental exercise test was performed on an upright electromagnetically-braked bicycle (Technogym, Gambettola, Italy). The patients exercised until exhaustion (dyspnea or fatigue). Heart rate was continuously recorded and arterial blood pressures were determined using the sphygmomanometric method. Cardiac output was measured at each workload by inert gas rebreathing (gas volume similar to the voluntary ventilation with a composition of 1% N2O, 0.2% SF6 and 36% O2 in N2 and a breathing rate of 30 breaths per minute). Before the study, the subjects had performed several tests to become familiarized with the rebreathing maneuver. The same protocol had been used to determine oxygen consumption (VO2) at each exercise step and maximum VO2.

Independent Variables

A consecutive isocaloric diet of either 70mmol per day or 250mmol per day sodium for seven days each, in a balanced randomized fashion.

Description of Actual Data Sample:
  • Initial N: 29 (15 males with HF and 14 controls of unknown gender)
  • Attrition (final N): 24 (12 in each group)
  • Age: 57±4 years
  • Ethnicity: Not described.

Other Relevant Demographics

Medications the HF patients were taking included the following:

  • ACE inhibitors (N=11)
  • Angiotensin receptor blockers (N=1)
  • Alpha/beta-adrenoreceptor blockers (N=5)
  • Beta-adrenoreceptor blockers (N=7)
  • Diuretics (N=10)
  • Spironolactone (N=4)
  • Digoxin (N=1)
  • Long-acting nitrates (N=2)
  • Statins (N=10)
  • Low-dose aspirin (N=10)

All of the medications remained the same during the two weeks. 

Anthropometrics

  • There were no significant differences between the two groups for height, weight, urinary sodium excretion rate, forced expiratory volume and forced vital capacity ratio
  • There was a significant difference in the VO2 max and the ejection fraction between the HF and control groups (19.9±2.3 vs. 30.9±2.6; P≤0.005 and 0.26±0.02 vs. 0.63±0.02; P≤0.0001, respectively)
  • Within the HF group, six were at NYHA Functional Class II and six were at Class III. For eight, the HF diagnosis was ischemic and for four, it was idiopathic. 

Location

Copenhagen, Denmark.

Summary of Results:

Variables

 

Treatment Group: Low Sodium
(Measures and Confidence Intervals)

Treatment Group: High Sodium
(Measures and Confidence Intervals)

Statistical Significance   of Group Difference

Control Group: Low Sodium
(Measures and Confidence Intervals)

Control Group: High Sodium
(Measures and Confidence Intervals)

Statistical Significance of Group Difference

Weight (kg)

90.3±4.1

91.7±4.0

P≤0.005

88.4±4.2

89.5±4.2

P≤0.05

PV (ml), seated

3,023±268

3,264±243

P≤0.05

3,290±139 

3,503±158

P≤0.05

PV (ml), supine

3,365±246

3,608±215

P≤0.05

3,565±150

3,831±185

P≤0.05

 

Seated PNa(mmol/L)

135±0.3*

138±0.5*

P≤0.05

138±0.7

138±0.4

NS

Supine PNa (mmol/L)

136±0.5

139±0.5

P≤0.05

138±0.8

138±0.6

NS

Seated PK (mmol/L)

4.3±0.2

4.0±0.1

NS

3.9±0.1

3.9±0.1

NS

Supine PK (mmol/L)

4.3±0.1

4.0±0.1*

NS

4.0±0.1

3.9±0.1

NS

Hb (mmol/L), seated

8.8±0.2

8.2±0.2

P≤0.05

8.9±0.1

8.7±0.2

P≤0.05

Hb (mmol/L), supine

8.4±0.2

7.9±0.2

P≤0.05

8.6±0.2

8.3±0.1

P≤0.05

Hct (%), seated

44±1

42±1

P≤0.05

46±1

44±1

P≤0.05

Hct (%), supine

42±1

39±1

P≤0.05

43±1

42±1

P≤0.05

Albumin (g/L), seated

42±1

40±1*

P≤0.05

43±1

42±1

P≤0.05

Albumin (g/L), supine

40±1

39±1

NS

41±1

40±1

P≤0.05

Creatinine (µmol/L), seated

110±6

102±5

P≤0.05

99±4

96±3

NS

Creatinine (µmol/L), supine

108±6

101±5

NS

100±4

96±3

P≤0.05

BUN (mmol/L), seated

8.4±1.4

5.9±0.5

P≤0.05

6.3±0.2

5.7±0.3

P≤0.05

BUN (mmol/L) supine

8.3±1.4

5.9±0.5

P≤0.05

6.2±0.2

5.5±0.3

P≤0.05

CI (1·min-1·m-2), seated

1.71±0.10*

1.94±0.13*

P≤0.05

2.15±0.10

2.44±0.12

P≤0.05

CI (1·min1·m-2), supine 

2.08±0.13*

2.22±0.11*

P≤0.05

2.65±0.11

2.77±0.11

P≤0.05

HR (beats/min), seated

66±3

62±3

NS

67±2

64±2

NS

HR (beats/min), supine

63±3

59±3

NS

59±2

59±2

NS

SVI (ml/m2),  seated

26±2*

32±2

P≤0.05

33±2

39±3

P≤0.05

SVI (ml/m2),  supine

34±2*

38±3*

P≤0.05

45±2

47±2

P≤0.05

MAP (mmHg),  seated

80±2*

80±2*

NS

94±2

94±3

NS

MAP (mmHg),  supine

82±1*

82±2*

NS

91±2

93±3

P≤0.05

PP (mmHg),  seated

34±2

38±3

P≤0.05

38±2

44±3

P≤0.05

PP (mmHg),  supine

40±2

43±3

NS

44±3

48±2

P≤0.05

TRP (dyn·s·cm-5),  seated

1,854±139

1,628±114

P≤0.0501

1,716±72

1,512±66

P≤0.05

TRP (dyn·s·cm-5), supine

1,563±116

1,430±79

NS

1,339±69

1,321±68

NS

LA diameter (mm), seated

38±2*

40±1*

P≤0.05

34±1

35±1

P≤0.05

LA diameter (mm), supine

42±2*

42±2*

NS

38±1

39±1

NS

NE (pg/ml),  seated

503(376-673)*

336 (247-458)*

P≤0.05

254 (204-317)

185(131-260)

P≤0.05

NE (pg/ml),  supine

310 (218-440)*

236 (161-345)

P≤0.05

182 (141-235)

153 (111-210)

NS

Epi (ng/ml),  seated

0.045 (0.025-0.06)

0.035 (0.02-0.6)

NS

0.02 (0.02-.04)

0.03 (0.02-0.04)

NS

Epi (ng/ml),  supine

0.025 (0.01-0.045)

0.02 (0.015-0.03)

NS

0.01 (0.01-0.02)

0.015 (0.01-0.02)

NS

ANG II (pg/ml), seated

21.0 (12.5-35.5)

9.6 (5.2-17.9)

P≤0.05

16.3 (12.6-20.9)

6.2 (4.6-8.5)

P≤0.05

ANG II (pg/ml), supine

14.3 (9.1-22.4)

6.2 (3.3-11.8)

P≤0.05

10.8 (8.1-14.3)

4.6 (3.4-6.1)

P≤0.05

Pro-BNP (picomol/L), seated

28.5 (14-34.5)*

29.5 (14-97)*

NS

1.5 (1-9)

7.5 (3.5-12)

NS

Pro-BNP (picomol/L), supine

26.5 (13-36.5)*

30.5 (13-107)*

NS

2.5 (1-5)

2.5 (1.5-10.5)

NS

 * Significant between groups (HF vs. control); P<0.05.

Other Findings

  • Sodium balance was achieved the last three days at each level of sodium intake. There were no significant differences in sodium excretion between the groups.
  • HF patients exercised 585±87 seconds on low and 617±88 seconds on high sodium intake (NS), while respective values for controls were 981±88 and 988±94 seconds (NS). The effect of sodium was significant on CI, SVI and TPR, at rest on the bicycle and during low- and high-intensity exercise, whereas MAP remained unaffected. The relative response attenuated with increasing workloads, although this was significant only for SVI and HR in HF patients.
Author Conclusion:
  • The renal, hemodynamic and neuroendocrine responses to alteration in sodium intake are similar in patients with medically-treated compensated HF and in healthy indviduals
  • High sodium intake was tolerated without any excessive sodium and water retention
  • The observation that high sodium intake improves cardiac performance, induces peripheral vasodilatation and suppresses the release of vasocontrictor hormones does not support the advice for medically-treated compensated HF patients to restrict dietary sodium.
Funding Source:
Government: Danish Research Council
Not-for-profit
0
Foundation associated with industry:
Reviewer Comments:
  • Unfortunately, the paper did not elaborate on the dietary aspect of the study
  • Since the subjects were in sodium balance for the last three days of each level of sodium intake, one assumes that they were on a controlled feeding study
  • Another criticism is that the accuracy of the 24-hour urine collections were not reported
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) 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
  3.4. 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? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  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.) Yes
  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? No
  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? ???
  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)? 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? No
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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes