Increased Salt Intake for Orthostatic Intolerance Syndromes: A Systematic Review and Meta- Analysis

Increased Salt Intake for Orthostatic Intolerance Syndromes: A Systematic Review and MetaAnalysis Elaine A. Loughlin, MB, BCh, BAO, Conor S. Judge, MB, BCh, BAO, Sarah E. Gorey, MB, BCh, BAO, Maria M. Costello, MB, BCh, BAO, Robert P. Murphy, MB, BCh, BAO, Ruairi F. Waters, MB, BCh, BAO, Diarmaid S. Hughes, MB, BCh, BAO, Rose Ann Kenny, MD, Martin J. O’Donnell, PhD, Michelle D. Canavan, PhD HRB-Clinical Research Facility, National University of Ireland Galway, Galway, Ireland; Galway University Hospital, Newcastle Road, Galway, Ireland; Wellcome Trust − HRB, Irish Clinical Academic Training, Dublin, Ireland; Mercer’s Institute for Successful Ageing, St. James’s Hospital, Dubline, Ireland.


INTRODUCTION
Orthostatic hypotension is defined as a sustained fall in systolic blood pressure of a least 20 mm Hg or a fall in diastolic blood pressure of at least 10 mm Hg within 3 minutes of standing. 1 Orthostatic hypotension is a common condition affecting 18.4% of community-dwelling older adults and 22.2% of adults in long-term care facilities. 2 However, prevalence varies across studies. It can be a debilitating disorder with an increased risk of falls, major injury, and increased morbidity and mortality. 3,4 Management of this condition is challenging, with many therapies having adverse side effects, including supine hypertension. 5 Increased salt intake is a cornerstone recommendation in the management of orthostatic intolerance syndromes across clinical guidelines, 6−11 including a Class I (Level C) recommendation in the European Society of Cardiology-Treatment of Syncope: Orthostatic Hypotension guidance. 6 However, guidelines vary on the amount of salt recommended (6-10 g/d), none reference clinical trial evidence to support this recommendation, and some include statements regarding the uncertain benefits and risks of long-term treatment with high salt intake (Table 1). Conversely, hypertension and cardiovascular prevention guidelines recommend low salt intake (<5 g/d). 12 Accordingly, an estimate of the net benefit of increased salt intake in patients with orthostatic hypotensionintolerance syndromes is required. 13 To address this gap, we performed a systematic review and meta-analysis to determine the effectiveness and safety of increased salt intake among patients with orthostatic intolerance syndromes.

Objectives
We aimed to synthesize the evidence of the efficacy and safety of increased salt intake as a therapeutic intervention in patients with orthostatic intolerance syndromes.

Preparing Our Systematic Review
We adhered to the Cochrane Handbook for Systematic Reviews of Interventions. 14 The review protocol was registered with PROSPERO, CRD42019121330.

CLINICAL SIGNIFICANCE
In patients with orthostatic intolerance syndromes, systematic review and meta-analysis showed that increased salt intake causes a short-term increase in blood pressure and time to presyncope during orthostasis. Increased salt intake improved symptoms of orthostatic intolerance in short-term studies. There is no report on the effect of long-term increased salt intake on falls or cardiovascular risk. Studies are short-term, small, and of low methodological quality.

Search Strategy and Selection Criteria
We searched PubMed, EMBASE, and CINAHL databases from database inception to January 17, 2019. We also searched the bibliographies of retrieved review articles from PubMed to identify additional relevant papers. Reviewers independently screened titles and abstracts using the Rayyan web software. 15 Following this, full-text articles were assessed for eligibility, and disagreements were resolved by consensus.

Eligibility Criteria
Studies were eligible if they included patients with orthostatic hypotension, falls, syncope or presyncope resulting from orthostatic intolerance, or reflex syncope. We also included postural orthostatic tachycardia syndrome and orthostatic tachycardia due to the similarities in treatment with orthostatic hypotension, thereby including a diverse group of orthostatic intolerance syndromes. 16 The intervention of interest was increased salt intake in the form of oral salt supplementation or intravenous saline infusion. Studies required either a placebo or alternative control group (or period) and at least 1 of the following outcome measures: rate of falls or injuries; rate of syncope or presyncope; change in symptoms; change in orthostatic intolerance; change in supine or orthostatic systolic blood pressure; change in supine or orthostatic heart rate; or adverse effects. We included all interventional clinical studies of human participants published in peer-reviewed journals in English.

Data Extraction and Measurements
Data were extracted by reviewers independently in an unblinded fashion, using a predetermined standardized data extraction form. Our primary outcome measures were the effect of salt on falls or injuries and rates of syncope or presyncope. Secondary outcome measures included the effect of increased salt intake on symptoms and other measures of orthostatic intolerance, the effect on physiological parameters including changes in blood pressure and heart rate, and the adverse effects of increased salt intake.

Quality Assessment and Publication Bias
The quality of the evidence and recommendations of the included studies were assessed using the GRADE guidelines and rated as very low, low, moderate, or high-quality. 17

Data Synthesis and Statistical Analysis
We collected descriptive data for a Characteristics of Studies table. The standardized mean difference (SMD) associated with increased salt intake was calculated for head-up tilt orthostatic tolerance or time to presyncope, seated or supine systolic blood pressure, and seated or supine heart rate. The mean difference following intervention was calculated for head-up tilt/standing systolic blood pressure, and head-up tilt/standing heart rate. The effect of the intervention on symptoms of orthostatic intolerance, and adverse effects were recorded. Weighted pooled treatment effects were calculated using a fixed effects (FE) model. 18 The variability across studies as a result of heterogeneity was estimated with the test for heterogeneity (I 2 ) statistic. Statistical analysis was performed using the Metafor package on R Statistical Software (V3.4.3). 19

Study Selection
Our initial search retrieved 1168 articles. Following review, 14 studies 20−31 including 391 participants satisfied full eligibility criteria; see the meta-analyses of observational studies in epidemiology (MOOSE) flow diagram (Supplementary Figure S1, available online).

Description of Included Studies
We included 11 single-arm interventional studies, 1 randomized double-blind placebo-controlled trial, 1 randomized crossover trial, and 1 open-label randomized trial. We report characteristics of included studies in Table 2.
A variety of methods were used to investigate the effect of increased salt intake on blood pressure. Ten studies (n = 322) used a head-up tilt method, 2 used an active stand (n = 33), and 2 assessed seated or supine blood pressure only (n = 36). The method of carrying out a head-up tilt differed across studies (Supplementary Table S1, available online).

Intervention
Increased salt intake was achieved through oral intake in 11 studies (table salt or slow sodium tablets) (range 1.2-10.5 g) and intravenously in 3 studies, using a saline infusion (6.3-9 g). Three studies included a control group. All other studies compared to a control period before salt intervention.

Primary Outcomes
Effect of Salt Intake on Falls or Injuries. No study reported on the effect of increased salt intake on the rate of falls or injuries.
Effect of Salt Intake on Orthostatic Tolerance and Time to Presyncope. Five studies reported data that were amenable to meta-analysis. Pooled analysis of these 5 studies (n = 164; syncope [n = 152] and orthostatic hypotension [n = 12]) showed higher salt intake increased orthostatic tolerance or time to presyncope by 1.57 minutes (95% confidence interval [CI], 1.26-1.88) I 2 = 97.2% (Figure 1). A pooled analysis looking at individual populations (i.e., syncope vs orthostatic hypotension) was not possible because of low study numbers.

Secondary Outcomes
Effect of Increased Salt Intake on Symptoms of Orthostatic Intolerance. Among studies reporting on orthostatic intolerance symptoms following increased salt intake (6 studies, 91 participants), 62.3% (95% CI, 51.6 to 72.6), I 2 = 97.2%, reported improvement (or resolution) in symptoms after a mean follow-up of 44.3 days. No study reported on symptoms beyond 60 days. In the only randomised placebo controlled trial (n=20) reporting on symptoms, symptomatic improvements were reported in 8/10 in the salt supplement group and 3/10 in the placebo group, relative risk (RR) 2.67 (95% CI, 0.98 to 7.22) after 8 weeks. One study used a questionnaire which was reported to be of demonstrated validity and reliability, 20     heart rate before and after intervention was available for 5 studies, and these were pooled for analysis (n=60; syncope [n = 32] and orthostatic hypotension or orthostatic tachycardia [n = 28]). Mean seated or supine heart rate did not change significantly after salt intervention: À0.08 (95% CI, Effect of Increased Salt Intake on Mean Difference in the Mean Change in Head-up Tilt or Standing Heart Rate. T a gg e d P Mean change in head-up tilt or standing heart rate before and after increased salt intake was reported in 4 studies (n=79; syncope [n = 66] and orthostatic tachycardia [n = 13]). Pooled analysis demonstrated that following increased salt intake, there was a À3.97 beats/ min change in the mean change in head-up tilt or standing heart rate (95% CI, À4.08 to À3.86), I 2 : 99.7% (Supplementary Figure S3).
Adverse Effects of Increased Salt Intake. The safety and adverse effects of increased salt intake were reported in 6 studies, n=72. Of those, 4 reported no adverse events with increased salt intake (n=32), 21,22,27 1 reported poor tolerance in 2 of 30 patients, 20 and 1 reported that most patients experienced nausea with salt capsules (n=10). 22 Supine hypertension as a potential adverse effect of salt supplementation is reported on above. No study addressed the long-term cardiovascular risk or other safety outcomes of increased salt intake.

Quality of Evidence/Publication Bias
The quality of the evidence was reported as "very low"/ "low." The small participant numbers and poor methodological quality contributed to this assessment. Only 3 trials were randomized. There was no blinding of outcome assessment. There was substantial or considerable heterogeneity among studies as demonstrated by the I 2 . Publication bias could not be assessed because there were less than 10 studies available in each of the outcome measures.

DISCUSSION
Our systematic review supports a short-term pressor effect of increased salt intake in the management of orthostatic intolerance syndromes. Pooled analyses indicate orthostatic tolerance or time to presyncope and systolic blood pressure were increased during orthostatic stress over a follow-up of 3-90 days. Symptom burden was also improved in small, short-term trials (longest follow-up of 8 weeks), but most studies did not include a control group. Increased salt intake resulted in a small increase in short-term seated or supine systolic blood pressure, and a reduction in orthostatic heart rate. We believe this reduction in heart rate represents the pressor effect of increased salt, which results in a lesser drop in orthostatic blood pressure and, thus, resulting in less of a rebound tachycardia. These observations may suggest a preferential effect of salt intake on orthostatic blood pressure, compared to supine blood pressure, potentially related to the effect of salt on increasing both circulating intravascular volume and increasing baroreceptor Figure 3 Forest plot of mean difference in mean change of head-up tilt/standing systolic blood pressure following administration of salt. Forest plot showing the effect of salt intervention during head-up tilt on the mean difference in the mean change of systolic blood pressure, n=45. The squares and bars represent the mean values and 95% confidence intervals of the effect sizes, and the size of the squares reflects the weight of the studies. The combined effect appears as a diamond and the vertical dashed line represents the line of no effect. sensitivity and peripheral vascular resistance. 21 We could not determine the longer-term efficacy and safety, or the long-term cardiovascular risk of increased salt intake because of the absence of long-term trials.
Included studies were small with short-term follow up, were of low and very low quality, and considerable clinical and statistical heterogeneity was observed.. Pooled analyses were possible on only a small number of relevant outcomes from a small number of studies. Additionally, subgroup analysis by individual orthostatic intolerance syndromes was not possible. There were large differences in study design, particularly in the methods of carrying out an orthostatic challenge, which limits the validity of combining studies.
There are limitations to the external validity of these findings, given that participants were young with few comorbidities and had few existing medications. It is especially difficult to ascertain whether they can be applied to an older, comorbid population. As many older adults with orthostatic hypotension would also be recommended lowsalt diets (especially those with co-existing hypertension or heart failure), there is clinical uncertainty about the risk-tobenefit ratio of long-term high-salt diets.
This work highlights the paucity of high-quality data supporting a cornerstone recommendation in the management of orthostatic intolerance syndromes. Our systematic review reports an absence of evidence, rather than evidence of absence, of the long-term clinical benefit of increased salt intake in orthostatic intolerance syndromes (e.g. on incidence of recurrent falls). Our review provides evidence for short-term improvements in orthostatic intolerance symptoms, but meta-analysis included small numbers of participants (n=91) and only one small trial was placebo controlled (n=20), which reported improvement/ resolution of symptoms in 30% of those receiving placebo. We do not suggest that current guidelines change, but, rather, should prompt more rigorous long-term evaluation of increased salt intake on clinical outcomes (e.g. falls, syncope) in relevant patient populations. Clinical trials are also required to determine the optimal amount of salt intake in patients with orthostatic intolerance syndromes (i.e. dose-finding studies), and whether regimens should vary by population. The need for high-quality randomized controlled trials of dietary intervention is being increasingly recognised, especially when modifying an essential nutrient or electrolyte. 32 33 There are ongoing large clinical trials of sodium reduction in populations with heart failure and for secondary stroke prevention. 34−36 There is also controversy about the optimal salt intake in general populations. While the WHO recommend low salt intake (<5g/day of salt) in the entire adult population, 37 based largely on clinical trials of blood pressure, prospective cohort studies report a J-shaped association of salt intake and cardiovascular events/mortality with the lowest risk at a moderate intake range (~7.5-12.5g/day of salt). 38 Findings from prospective cohort studies, and the absence of definitive randomised controlled trials, has resulted in calls to undertake large clinical trials comparing low salt intake to moderate intake in general populations. 39 In conclusion, our meta-analysis provides low-quality evidence of a short-term improvement in orthostatic intolerance with increased salt intake. There were no clinical trials demonstrating the efficacy and safety of increased salt intake on long-term clinical outcomes. Our findings highlight the need for robust randomized controlled trials, particularly in older adults with symptomatic orthostatic intolerance syndromes.  Nil further details Self-administered: no diary kept Zhang, 2012 Seated Supine Seated BP measured before and after salt intake.
Nil further details Self-administered: no diary kept *Table demonstrating method of carrying out an orthostatic challenge. Author and year of publication are listed in the first column, followed by method of assessing orthostatic intolerance, procedure used, method of measuring blood pressure and heart rate and whether this was intermittent or continuous, and method of recording salt intake. BP = blood pressure; ECG = electrocardiogram; HR = heart rate; HUT = head-up tilt; IV = intravenous; N/A = not applicable; NaCl = sodium chloride.