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Does a Low Sodium Diet Improve Asthma Control?

A Randomized Controlled Trial

¹ Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; and ² Pharmacy, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

Correspondence and requests for reprints should be addressed to Zara Pogson, M.R.C.P., Division of Epidemiology and Public Health, University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Nottingham, NG5 1PB, UK. E-mail: zara.hoare{at}nottingham.ac.uk

	ABSTRACT

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Rationale: Observational studies and initial randomized trials have indicated that a low sodium diet may improve asthma control.

Objectives: We tested the hypothesis that a low sodium diet would improve asthma control over a 6-week period.

Methods: Participants with a physician diagnosis of asthma and measurable bronchial reactivity to methacholine entered a randomized double-blind placebo-controlled trial. All adopted a low sodium diet and were randomized to receive either 80 mmol/day of oral sodium supplements (normal sodium intake) or matched placebo (low sodium intake) for 6 weeks. The primary outcome was change in bronchial reactivity to methacholine; secondary outcomes were change in lung function, morning and evening peak expiratory flow, asthma symptoms score, daily bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire score, and atopy.

Measurements and Main Results: A total of 220 individuals entered the study, of whom 199 completed the protocol. In the low sodium–intake group, mean daily urinary sodium excretion decreased by 20 mmol (SD, 64 mmol) and in the normal-sodium-intake group increased by 28 mmol (SD, 74 mmol). There were no differences between the two groups in the primary or secondary outcome measures; the mean difference in bronchial reactivity between the low- and normal-intake groups was –0.03 doubling doses of methacholine (95% confidence interval, –0.60 to 0.53).

Conclusions: The use of a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity to methacholine.

Clinical trial registered with www.controlled-trials.com (ISRCTN80771653).

Key Words: asthma management • sodium • controlled trials

AT A GLANCE COMMENTARY TOP ABSTRACT AT A GLANCE COMMENTARY METHODS RESULTS DISCUSSION REFERENCES   Scientific Knowledge on the Subject Small clinical trials have suggested that a low sodium diet may improve asthma control. What This Study Adds to the Field This study demonstrates that a low sodium diet as an adjunctive therapy to normal treatment has no additional therapeutic benefit in adults with asthma and bronchial reactivity.

 
Asthma prevalence has increased in many countries over recent decades (1–3), and is higher in areas with a more affluent Western lifestyle (4, 5). One characteristic of more developed countries is higher levels of dietary sodium intake (6, 7), and Burney (8, 9) hypothesized that the elevated levels of dietary sodium intake may contribute to the higher prevalence of asthma seen in these countries. However, although cross-sectional epidemiologic studies of the association between dietary sodium intake and asthma have demonstrated inconsistent results (8–20), small intervention studies using a low sodium diet in individuals with asthma have demonstrated an improvement in bronchial reactivity, asthma symptoms, bronchodilator consumption, spirometry, and peak expiratory flow rate (PEFR) in several (21–24), although not all (25), reports. Recent studies have also reported reduced bronchoconstriction after exercise in people with exercise-induced asthma who were placed on a low sodium diet (26–31). A Cochrane review (32) concluded that current studies of the effect of a low sodium diet in individuals with asthma suggest a possible improvement in pulmonary function, but larger studies are needed to clarify the potential of a low sodium diet as a therapeutic option for asthma. The mechanism for this proposed effect is poorly understood but may involve modification of membrane sodium transport, which impacts on the contractile properties of airway smooth muscle (33). We therefore performed a randomized controlled trial to investigate if adopting a low sodium diet improved asthma control in 220 adults with asthma and bronchial reactivity to methacholine.

	METHODS

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Participants
Participants were aged 18 to 65 years old with a physician diagnosis of asthma and recruited from general practices in Nottingham and the University of Nottingham asthma register. Exclusion criteria were the use of oral steroids currently or within the past 4 weeks, an exacerbation of asthma requiring a change in regular medication within the past 4 weeks, a lifetime smoking history greater than 10 pack-years, current use of diuretics and angiotensin-converting enzyme inhibitors, and current or planned pregnancy within the trial period. Individuals were invited to participate by letter, and those who were eligible were invited to attend for a screening visit at Nottingham City Hospital where they were provided with detailed information about the trial; if they consented to take part, they entered a 1-week run-in period. After this, participants attended for a baseline visit where a bronchial challenge was performed. They were randomized if bronchial reactivity to inhaled methacholine was present. A total of 220 (18.5%) of the 1,189 individuals who expressed an interest in the study eventually entered the trial (Figure 1). Participants attended 6 weeks later for a final visit. The duration of 6 weeks was chosen based on previous studies (21–31). Other than a fee to cover travel expenses, the participants received no payment for their involvement in the study. The study was approved by the Multi-Centre Research Ethics Committee for Wales (UK).

View larger version (20K): [in this window] [in a new window]   Figure 1. Flow of participants through the study. *Side effects: headache, n = 1; abdominal symptoms, n = 1.

Study Objectives and Outcomes
The study hypothesis was that a decrease in daily sodium intake would improve clinical control of asthma. The primary outcome was change in PD₂₀ (inhaled dose of methacholine that provoked a 20% fall from baseline FEV₁ up to a maximum dose of 24.5 µmol) over 6 weeks. Secondary outcome measures were change in FEV₁, FVC, mean morning and evening PEFRs, morning and evening symptoms score, morning and evening bronchodilator use, Juniper Standardized Asthma Quality of Life Questionnaire, and atopic status over the same time period. A complete description of the study measurements is provided in the online supplement.

Statistical Analysis and Power
Primary analysis was on an intention-to-treat basis, assuming a 1-doubling-dose deterioration in bronchial reactivity for any individual who had a worsening in their asthma, as assessed by an increase in their asthma medication or the use of oral corticosteroids within 2 weeks before the end of the study; and baseline values were used for those who dropped out for other reasons. PD₂₀ values were log transformed and analyzed using an unpaired t test. Secondary outcomes were also analyzed on an intention-to-treat basis using baseline values for those who dropped out, with parametric (unpaired t test) and nonparametric tests (Mann-Whitney U test) as appropriate. Multiple linear regression was used to adjust for apparent differences between groups at baseline. We explored these data with post hoc analyses, which are discussed in the online supplement.

The study had 90% power to detect a difference between groups of 0.7 doubling doses for bronchial reactivity, a difference of a 110-ml increase in FEV₁ and a 17-L/minute increase in morning peak flow using a standard deviation for change over 6 weeks in PD₂₀ of 1.5 doubling doses, FEV₁ (240 ml), and morning peak flow (37 L/min), using data from our previous study (35) and taking P < 0.05 as statistically significant. Statistical assessment was performed with the Statistical Package for the Social Sciences (version 12; SPSS, Inc., Chicago, IL) and Stata SE 9.0 (Stata Corp., College Station, TX).

Some of the results of these studies will be reported in the form of an abstract at the American Thoracic Society meeting in 2008.

	RESULTS

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Participants were recruited between February 2006 and June 2007 (Figure 1). A total of 11,971 letters were sent out and, of these, 1,189 responses were received. Five hundred fifty-three interested individuals were invited to attend a screening visit, 486 potential participants attended a screening visit, and 220 individuals were randomized. One hundred ninety-nine individuals attended all of the study visits and completed the study. The baseline characteristics of study participants are similar for both groups except that those randomized to the normal sodium group had a higher proportion of females (Table 1).

Primary and Secondary Outcomes
In intention-to-treat analysis, there were no differences between the two groups in any of the primary or secondary outcomes (Table 2). The mean difference in change in PD₂₀ between those who were allocated to the LSI compared with the NSI was –0.03 doubling doses of methacholine (95% confidence interval, –0.60 to +0.53). Adjustment for the baseline differences in sex between the two intervention groups by linear regression or stratifying by sex (test for interaction, P = 0.17) made no appreciable difference to the results (results not shown). There was no difference between the two groups using a per protocol analysis (Table 3). There was also no difference between the two groups if the primary analysis was restricted to those whose baseline 24-hour urinary sodium excretion was higher than the median value or who were stratified by the use of inhaled corticosteroids or atopic status. There was no correlation between change in 24-hour urinary sodium excretion and change in PD₂₀, either in the total study population (r = 0.09, P = 0.21) or in the two intervention groups analyzed separately (LSI r = 0.10, P = 0.35; NSI r = 0.09, P = 0.37).

During the study, five participants in the LSI group and six participants in the NSI group had an exacerbation of their asthma, treated by their primary care practitioner. One participant in the LSI group was admitted to hospital with exacerbation of his asthma. With respect to nonasthmatic complications, three participants in the LSI group and one participant in the NSI group had abdominal symptoms. One participant on the LSI group was admitted to hospital with musculoskeletal chest pain and dropped out of the study. One participant in the NSI group reported headaches and discontinued the tablets.

	DISCUSSION

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Summary of Findings
We observed no difference in outcome measures related to asthma activity in adults with asthma and bronchial reactivity who adopted a low sodium diet for 6 weeks compared with those who did not, despite a final difference in daily sodium excretion of 50 mmol between those who were allocated to the low sodium intake and those who received a normal sodium intake.

Strengths of the Study
This study is the largest randomized placebo-controlled trial of the effect of a low sodium diet on asthma control to date. We used bronchial reactivity as the primary outcome measure because it is an objective measure of asthma activity (36). The study was well powered with 90% power to detect a 0.7-doubling-dose difference between treatment group changes in bronchial reactivity. Blinding was good as demonstrated by the fact that 74 to 76% of participants did not identify the intervention they were allocated to. Retention in the study was good, with a dropout rate of 10%.

Limitations of the Study
The major limitation of this study is the fact that the participants allocated to the LSI did not achieve the planned decrease in dietary sodium consumption of 80 mmol per day, and the difference in daily sodium intake as assessed by 24-hour sodium urinary excretion between the two groups was 50 mmol at the end of the study. This is probably due to the fact that the participants already had a relatively low baseline sodium intake, with a median daily sodium urinary excretion of 117–119.5 mmol compared with the geometric mean for the local population of approximately 168 mmol in 1991 (10). During the study recruitment period, people often stated that the challenging low sodium diet was their reason for declining entry into the study and so we concluded that a low sodium diet is an unattractive proposition for many people, even if it may lead to health benefits. However, in a post hoc analysis, there was no association between change in 24-hour sodium urinary excretion and change in bronchial reactivity, and restricting the analysis to those who were above the median daily sodium urinary excretion at the beginning of the study also showed no association between sodium intake and bronchial reactivity. These analyses support the conclusion that there is no strong association between an achievable change in dietary sodium intake and asthma control in our study population. Although approximately 74% of participants in our study had asthma that required inhaled corticosteroids, similar to that observed in a wider nonselected population (37), it is likely that our study population was highly self-selected, which may present some issues with the generalizability of our data. In particular, the relatively low daily dietary sodium intake of individuals who participated in our trial compared with that of the general population (10) suggests that participants in our study are more likely to be relatively health conscious, and therefore may also differ from the general population in other ways that we were unable to measure.

Other Studies
Our data require consideration in the context of the preceding studies, which suggested that a low sodium diet may improve measures of asthma control. The potential benefits of low sodium intake have been assessed in individuals with asthma (21–25) and in a subgroup of people with exercise-induced asthma (26–31). An initial unblinded study (23) gave 15 participants (10 participants with asthma and 5 control subjects) sodium supplementation in the form of both sodium tablets and also by adding salt to food for 1 month. Bronchial reactivity was measured by the provocative concentration of histamine needed to reduce FEV₁ by 20% (PC₂₀) and the PC₂₀ decreased from 7.5 to 5.2 mmol/L over the course of the study. The baseline daily sodium urinary excretion was 156 mmol and rose to 216 mmol by the end of the study. After this initial study, the subsequent studies used a randomized placebo-controlled crossover study design (21, 22, 24, 25). The first of these was a study of 36 individuals with asthma (21), with all participants consuming a low sodium diet for a total of 4 weeks, and then receiving placebo tablets for 2 weeks and 80 mmol of sodium (in the form of slow sodium) for 2 weeks. In the low dietary sodium limb (when receiving placebo tablets), daily urinary sodium excretion reduced by approximately 33 mmol from a baseline of 106 mmol. In the normal sodium limb (when receiving sodium tablets), daily urine sodium increased from baseline by approximately 45 mmol. There was a 1.5-doubling-dose improvement in PD₂₀ to histamine on the low sodium phase of the study compared with the sodium supplementation phase in men but not women. Medici and colleagues (24) placed 14 individuals with asthma on a low sodium diet and gave them placebo tablets or 157 mmol of sodium a day in the form of sodium chloride for 3 weeks using a crossover trial study design. The baseline mean daily sodium urinary excretion was 119 mmol. During the low sodium limb, the mean daily sodium urinary excretion decreased by 40 mmol, and during the high sodium limb, the mean daily sodium urinary excretion increased by 18 mmol. There was no significant improvement in bronchial reactivity to methacholine, but FEV₁ fell by 270 ml and PEFR decreased by 7 L/minute during the high sodium limb compared with the low sodium limb. The differences in daily urinary excretion of 58 and 79 mmol between the low sodium and the control limbs of these two studies (21, 24) are similar to our comparable figure of 50 mmol. However, our study was over five times larger than these studies, and we were unable to detect any association between measures of asthma control and daily urinary sodium excretion using either a priori or post hoc analyses.

Carey and coworkers (22) recruited 22 male participants with asthma who were given advice on adopting a low sodium diet, and who were exposed for a 5-week period to placebo tablets or a relatively high dose of sodium (200 mmol/d), again using a crossover study design. The baseline mean daily sodium urinary excretion was 159 mmol, and the mean daily sodium urinary excretion decreased by 88 mmol during the low sodium limb and increased to 292 mmol during the high sodium limb. There was a significant deterioration in asthma control during the high sodium limb; the PD₂₀ to methacholine dropped by a 0.73 doubling dose and the FEV₁ was reduced by 210 ml compared with the low sodium limb. In addition, the median symptom score improved by 0.6 units and bronchodilator use decreased by a median 1.3 puffs per day during the low sodium limb compared with the high sodium limb. We speculate that the changes seen after manipulation of sodium intake in this study are largely due to loading with sodium chloride, and so these data are not directly comparable with our own.

The only negative crossover study of the impact of a low sodium diet on control of asthma (25) was small and underpowered. There have also been several studies assessing the impact of a low sodium diet on exercise-induced asthma (26–31), which suggest that adopting a low sodium diet for 1 to 2 weeks results in a marked improvement in lung function 5 minutes after an exercise challenge, an effect that is possibly mediated by changes in postcapillary blood volume and pulmonary inflammation (30).

Any intervention that may improve control of asthma requires careful evaluation, particularly in the light of negative studies such as ours which have the potential to discourage further studies in this field. We selected an intervention that lasted for 6 weeks, a period that exceeds or is comparable to the published studies of manipulating sodium intake that have demonstrated a benefit on asthma control (21–24), but we are unable to exclude the possibility that a longer intervention period may have a beneficial effect on disease control. We selected individuals with demonstrable bronchial reactivity that had scope for improvement on a low sodium diet as reported by previous investigators (21–23) but are unable to reject the hypothesis that a low sodium diet may improve asthma control in specific subgroups with different asthma phenotypes of varying etiology or severity. The study had 90% power to detect a difference between treatment groups of 0.7 doubling doses in bronchial reactivity and 110 ml in FEV₁, and we are unable to exclude the possibility that a low sodium diet may result in improvements in bronchial reactivity or FEV₁ that are smaller than this. However, the upper limit of the 95% confidence limits suggests that the effect is unlikely to be greater than approximately half a doubling dose of inhaled methacholine, or up to 76 ml for FEV₁ in this study population, and we consider that this is not likely to be clinically important at the level of the individual patient relative to the benefits that can be derived from other interventions. On the basis of our data, it is also unlikely that there is a large sex-specific effect of a low sodium diet on asthma control, although the study was not powered to detect this interaction and we may have failed to detect effect modification by sex.

Conclusions
Our pragmatic randomized controlled trial of the role of a low sodium diet on asthma control did not show any evidence of a therapeutic benefit, despite a differential in 24-hour urinary excretion of 50 mmol between the intervention and control group at the end of the intervention in those who completed the study. We cannot exclude the possibility that a low sodium diet may improve asthma control in those who either consume higher baseline levels of dietary sodium or can achieve a greater decrease in dietary sodium intake than we observed. However, our data suggest that, despite the clear benefit of a low sodium diet on cardiovascular risk factors (38), there is no therapeutic benefit in the use of a low sodium diet based on a dietary information sheet on asthma control in our study population.

	Acknowledgments

 
The authors thank all of the primary care centers and volunteers who participated in the study, and Purba Choudhury for comments on the manuscript.

	FOOTNOTES

 
Supported by an Asthma UK project grant.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200802-287OC on May 1, 2008

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 18, 2008; accepted in final form April 21, 2008

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This Article Abstract Full Text (PDF) Online Supplement All Versions of this Article: 200802-287OCv1 178/2/132    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pogson, Z. E. K. Articles by Fogarty, A. W. Search for Related Content PubMed PubMed Citation Articles by Pogson, Z. E. K. Articles by Fogarty, A. W.