SalT supplementation in Older adults with Orthostatic intolerance Disorders (STOOD) trial: a study protocol for a feasibility randomised controlled trial

Abstract

Background

Orthostatic hypotension (OH) is a common cause of falls, and key source of morbidity and mortality due to injury (e.g. hip fracture). Current guidelines recommend increasing salt intake in patients with symptomatic orthostatic hypotension. However, the evidence underpinning this recommendation is poor, based primarily on small trials with very short-term follow-up (<8 weeks). High salt intake might improve quality of life and reduce the risk of falls, but might also increase the long-term risk of cardiovascular disease, in patients with OH.

Methods

STOOD is a two-group, parallel, open-label, randomised controlled, single centre trial. Adults aged ≥65 years with symptomatic orthostatic hypotension, and estimated moderate salt intake (based on screening questions) will be eligible. Exclusion criteria include uncontrolled hypertension (>180/110 mmHg), heart failure (NYHA class III/IV, or ejection fraction < 30%), loop diuretic use, chronic kidney disease (eGFR < 30 ml/min/1.73m²), hyponatraemia (serum sodium < 125 mmol), evidence based clinician recommendation of high or low salt diet, and inability to provide informed consent. Participants will be randomised to receive salt supplementation of 5 g encapsulated sodium chloride per day (in addition to usual care) or usual care alone. The primary feasibility outcome will be recruitment and retention of the target sample size of 48 participants. The primary efficacy outcome is change in orthostatic hypotension questionnaire score from baseline to 6-month follow-up.

Discussion

A recommendation for long-term higher salt intake may have adverse cardiovascular consequences, which necessitates robust evidence of efficacy and identification of the optimal range of salt intake associated with the greatest reduction in falls risk and lowest cardiovascular risk. Our study will establish the feasibility and acceptability of evaluating the intervention (salt supplementation) in a single centre, and provide preliminary evidence of treatment effect of salt supplementation for management of orthostatic hypotension.

Trial registration

ClinicalTrials.gov Identifier: NCT06188663. Registered on 17th December 2023

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s40814-026-01885-9.

Introduction

Orthostatic hypotension (OH) is a common cause of falls, and key source of morbidity and mortality due to injury (e.g. hip fracture) [1, 2]. Current guidelines recommend increasing dietary salt intake in patients with symptomatic OH [3]. While all guidelines recommend increased salt intake, there is considerable variation in quantity of salt advised (Table 1) [3, 6]. However, the evidence underpinning these recommendations is sparse, based primarily on small trials with very short-term follow-up, with the longest follow-up duration in a population with orthostatic hypotension being 56 days [9, 10].

Table 1.

Synopsis of current guidelines

Organisation	OH guidelines	CVD guidelines
European Society of Cardiology	10 g of salt (sodium chloride) per day [3]	Salt restriction to <5 g/day [4]
NICE	Increase salt intake—no amount advised (NICE)	Target 6 g salt/day (NICE)
American Society of Hypertension	6–10 g of sodium chloride (American Society of Hypertension) [5]
American Heart Association	Increase salt intake (no amount specified) [6]	Optimal goal is <1500 mg/day, but aim for at least a 1000 mg/day reduction in most adults (ACC/AHA) [7]
The European Federation of Neurological Societies	At least 8 g (150 mmol) of sodium chloride per day [8]

There is a lack of randomised controlled trial evidence evaluating salt supplementation for the management of OH, in particular in older adult populations, where incidence of OH is highest [9, 11]. The Food and Drug Administration (FDA) advise that drugs which may have utility in older adults should be evaluated in that population [12]. However, this guidance has not been followed for this dietary intervention.

While clinical trial evidence evaluating the optimal dose of salt for the management of symptomatic OH and the long-term effects is limited, the physiological rationale behind salt supplementation as an intervention to improve orthostatic tolerance is compelling. Studies demonstrate that salt loading leads to short-term expansion of extracellular volume [13, 14]. However, these physiological findings have not been replicated in older adults with symptomatic OH.

In contrast, there is robust evidence of increased cardiovascular risk at very high salt intake in the general population [15]. For the general population, current guidelines advise salt restriction, with the World Health Organisation (WHO) advising <5 g of salt/day, a target that directly conflicts with guidelines for symptomatic OH [16]. Moreover, hypertension guidelines recommend more judicious salt restriction, with the American Heart Association advising <3.75 g of salt (<1.5 g of sodium/day) [17, 18]. Given evidence that high salt intake is associated with increased cardiovascular risk, it is imperative that salt intake recommendations for adults with OH, are supported by robust evidence and consider the risk–benefit balance including falls and cardiovascular events [9].

In the case of symptomatic OH, a recommendation for long-term increases in salt intake (to high intake, which may have adverse cardiovascular consequences) necessitates the urgent need to evaluate whether there is net clinical benefit from long-term high salt intake. This is of particular importance in older adults with OH.

Methods

Study overview

The SalT supplementation in Older adults with Orthostatic intolerance Disorders (STOOD) trial (ClinicalTrials.gov NCT06188663) is a prospective, single centre, open-label, randomised controlled trial which will recruit adults, aged 65 years and above, with symptomatic orthostatic hypotension (Fig. 1). Participants will be recruited from hospital-based or community outpatient clinics in the catchment area of a tertiary referral hospital in Galway, Ireland. Eligible, consenting patients will be enrolled and randomised to salt supplementation and usual care or usual care alone (no change in salt intake). This trial will be conducted in compliance with the study protocol, principles laid down in the Declaration of Helsinki, and Good Clinical Practice guidelines as defined by the International Conference on Harmonization where applicable. Before participation, written informed consent will be obtained from each participant.

Fig. 1.

Study flow

Study population

STOOD will enrol approximately 48 participants. Inclusion criteria include age ≥65 years, symptoms consistent with orthostatic hypotension (e.g. lightheadedness), estimated moderate dietary salt intake (based on screening questions), willingness to supplement salt intake and written informed consent (Table 2). In addition, eligible patients must demonstrate evidence of an orthostatic drop in blood pressure (BP) (≥20/10 mmHg) at or within 4 weeks of randomisation visit. Key exclusion criteria are shown in Table 2.

Table 2.

Inclusion and exclusion criteria

Inclusion criteria

1. Adults ≥65 years of age 2. Documented history of orthostatic hypotension, defined by decrease in systolic blood pressure (SBP) of ≥20 mmHg or a decrease in diastolic blood pressure (DBP) of ≥10 mmHg within 3 min of standing when compared with blood pressure from the supine position, or at head-up tilt testing at randomisation visit or within 4 weeks prior to randomisation visit 3. A documented history of symptoms consistent with orthostatic hypotension including one of the following: light-headedness, dizziness, feeling faint, feeling like they may black out (pre-syncope) within 6 weeks 4. Baseline salt intake in moderate range (5–10 g/day) based on screening questions 5. Willingness to supplement sodium (salt) intake 6. Ability to provide written informed consent

Exclusion criteria

1. Severe supine hypertension (SBP ≥ 180 mmHg or DBP > 110 mmHg) from an average of three office readings at randomisation visit 2. A diagnosis of Heart Failure (New York Heart Association (NYHA) Class III or IV symptoms or known left ventricular ejection fraction 30%, if more than one echo eligibility is defined by most recent echo) 3. Chronic kidney disease (eGFR < 30 ml/min/1.73m2) based on laboratory reported eGFR measured within the last 6 months 4. Participants taking loop diuretics (defined as within previous 2 weeks) 5. Serum sodium < 125 mmol/L within last 3 months 6. Acute intercurrent illness 7. Prescribed high-salt diet (clinical indication other than for OH) or low-salt diet for evidence based clinical indication 8. Participant unlikely to comply with study procedures or follow-up visits due to severe comorbid illness or other factor (e.g. inability to travel for follow-up visits) in opinion of research team 9. Inability to provide informed consent in the opinion of the investigator (e.g. severe cognitive impairment)

Randomisation, treatment and follow-up

Enrolled patients will be randomised (web-based randomisation) in a 1:1 ratio between salt supplementation (intervention arm) and usual care alone. A minimisation strategy will be employed in randomisation to account for differences in age, sex and adjustment of anti-hypertensive/orthostatic hypotension therapy at screening (as part of routine clinical care).

Participants allocated to the intervention arm will take 5 g of encapsulated sodium chloride per day (in two divided doses). All participants will receive education on non-pharmacological management of orthostatic hypotension including physical counter-manoeuvres and fluid intake (2–3 L/day). Participants will be advised not to change their usual diet and specifically advised not to adjust dietary salt intake. Follow-up will occur at 1 month, and 6 months after enrolment. Schedule of events is outlined in Table 3. The encapsulated sodium chloride will be discontinued at 6 month visit. An extended follow-up visit will be conducted 12 months after enrolment. Criteria for withdrawal of salt supplementation is outlined in Table 4. Participants will be encouraged to complete remaining follow-up visits despite withdrawal.

Table 3.

Schedule of events

	T0	T1	Final study visit	Extended follow-up
			T2	T3
	Screening & Randomisation	4 weeks (±1 weeks)	6 months (±2 weeks)	12 months (±1 month)
Eligibility criteria/check	X
Informed consent	X
Patient demographics	X
Physical measurements	X	X	X
Blood pressure (3 office readings)	X	X	X
Orthostatic challenge: Active stand and head up tilt	X	X	X
Review ± adjustment of medications	X
Randomisation	X
Medications	X	X	X	X
OHQ	X	X	X	X
Salt questionnaire	X		X	X
24 ABPM	X	X	X
Morning fasting urine sample	X	X	X
FFQ	X		X
Blood biochemistry	X	X	X
Pro-BNP, hsTnT	X	X	X
Dispense study supplement	X	X
Adherence and outcomes		X	X	X1
Review of ABPM ± of medication review		X	X

OHQ Orthostatic hypotension questionnaire, ABPM ambulatory blood pressure monitor, FFQ food frequency questionnaire, Pro-BNP pro btype natriuretic peptide, hsTnT high-sensitivity troponin T

¹Events and changes to antihypertensives/OH pharmacotherapy only, adherence not applicable

Table 4.

Criteria for withdrawal

The study intervention will be withdrawn if:
1. Withdrawal from the study supplement is requested by the participant
2. Severe hypertension on ABPM (≥180 mmHg mean SBP or ≥110 mmHg mean DBP)
3. Physician recommendation for sodium restriction for an evidence-based clinical indication
4. Clinical symptoms or signs of new or worsening heart failure
5. Clinically unstable symptoms of orthostatic hypotension necessitating sodium supplementation in the opinion of the treating physician
The orthostatic hypotension questionnaire will be completed at withdrawal

Study outcomes

The primary outcome for the STOOD trial is recruitment and retention of the target sample size (48 participants). A key secondary feasibility outcome is adherence to the intervention (assessed through a pill count at follow-up visits), an essential metric to inform the feasibility of a definitive trial. Objective change in sodium will be assessed by change in urinary sodium excretion (formula-derived 24-h estimated sodium excretion from fasting morning urine sample).

The primary efficacy outcome is change in orthostatic hypotension score from baseline to 6-month follow-up. The Orthostatic Hypotension Questionnaire (OHQ) is a disease-specific, patient-reported, quality of life questionnaire and was chosen to capture the most clinically important consequences of OH and ensure that the patient experience is at the centre of the STOOD trial. There is inter-person variability in BP thresholds at which people develop symptoms of OH [19]; therefore, symptoms and the impact of these symptoms on daily activities, which is measured in the OHQ, is of most clinical relevance.

Secondary efficacy outcomes include change in: (i) clinical outcomes: individual components of the OHQ, rates of modification of OH pharmacotherapy and anti-hypertensive therapy, and fall events at 1 and 6 months; (ii) physiological measures of orthostasis: change in difference between supine and nadir systolic BP, standing BP at 1 min, 24 h mean BP measured (using 24-h ambulatory BP monitor); (iii) cardiovascular biomarkers (pro-BNP and troponin). Secondary outcomes are exploratory.

Statistical analysis plan

A recruitment of 48 or more participants per site in the feasibility study will provide evidence that the true recruitment rate is ≥37 per site per 15-month period (with an alpha 0.05 and 80% power). A sample size of 48 participants was estimated to assess the feasibility of recruitment for a definitive six-centre trial and report preliminary estimates for fall events over 2 years of follow-up. For example, a baseline falls rate of 0.325 fall events/patient/year (1) would require 350 participants in a definitive trial (80% power) to detect a 25% relative reduction in the falls.

Recruitment and retention rates will be reported using a CONSORT flow diagram. The primary analysis of the feasibility study will calculate the mean number of patients recruited and randomised per month (including only the months in which the centre is open to active recruitment). Retention percentage, number of participants followed up divided by number of participants randomised, will be measured at 1- and 6-month follow-up. Kaplan–Meier curves reporting the time from randomisation to loss to follow-up or withdrawal may be presented. Secondary outcomes will include adherence with study supplement. The proportion of participants who returned empty blister packs will be reported.

The primary efficacy outcome is change in orthostatic hypotension questionnaire score. Subgroup analyses for the primary outcome will be conducted by sex, use of OH pharmacological management, and responders versus non-responders. A secondary per-protocol analysis will also be carried out for all outcomes, with post-randomisation exclusions due to ineligibility, non-compliance, loss to follow-up, or missing data. An ANCOVA regression model will be used to estimate the treatment effect, with the OHQ score at the final study-specific visit as the response and adjusting for the baseline OHQ score. A similar approach will be used for the analysis of secondary outcomes, using appropriate generalised linear models. If there are any chance imbalances in the baseline distribution of important covariates between treatment groups, an adjusted secondary analysis will also be performed with the intention to treat dataset and the relevant covariates.

Progression criteria

A go/no go criterion of recruitment of 5 participants within 1 year was set. An acceptable retention rate will be considered 90%. An acceptable adherence rate will be ≥75% for the duration of trial intervention with salt supplementation.

Data monitoring

A data and safety monitoring board (DSMB), chaired by a clinician scientist with experience in clinical trials, will review interim analysis when 50% of participants have completed a 6-month follow-up. Rates of withdrawal from intervention due to hypertension or heart failure, other adverse events and clinical outcomes, e.g. injurious falls, will be considered by the DSMB. It will not affect statistical analysis for primary outcome (i.e. no adjustment to alpha) as there is no formal interim analysis for primary outcome.

Study administration

All study activities will be conducted and coordinated at the HRB Clinical Research Facility Galway (HRB-CRFG). All participants will provide written informed consent before any study-specific activities will be completed, and all data will be handled with strict privacy and electronic data security standards, using unique subject identifiers to prevent unauthorised identification of research participants. Pseudonymised data will be entered into a study-specific, secure, password-protected clinical trial database, with an audit trail.

Dissemination of information

The results of the STOOD trial will be presented at scientific meetings (local, national and international), patient-oriented meetings and published in peer-reviewed publications. The HRB-CRFG and investigators have the ownership of all data and results collected during the trial and have full rights to publication, without restriction. The dataset will not be made publicly available; instead, it will be maintained at HRB-CRFG and the investigators must review and approve all requests for access to the data.

Support

The STOOD trial is an investigator-initiated study, supported by a grant from the Health Research Board, Ireland. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Discussion

Orthostatic hypotension is estimated to affect almost 1 in 5 of community-dwelling adults over the age of 60 years [20]. The first-line management of OH includes a recommendation to increase salt intake (e.g. a target of 10 g of salt per day in those without hypertension) [3]. Currently this recommendation lacks robust evidence, particularly in the population most commonly affected by OH, older adults. Four single arm studies evaluated short-term salt supplementation in individuals with OH, with a mean age ranging from 33 to 43 years [10, 19, 21, 22]. FDA guidance from over 30 years ago advised that drugs likely to be used in older adults, should be evaluated in that population [12]. However, this guidance has not been followed for this dietary intervention.

In contrast, there is robust evidence of increased cardiovascular risk at very high salt intake in the general population [15]. Current guidelines advise salt restriction, with the WHO target (<5 g of salt/day) conflicting directly with guidelines for symptomatic OH [16]. This conflict is greater for those with hypertension, where guidelines recommend more judicious salt restriction [17, 18]. The 2019 dietary recommendations by the National Academy of Medicine (formerly the Institute of Medicine) acknowledge persistent knowledge gaps and call for evidence of the effect of dietary intakes on health outcomes across life stages [23]. It is imperative that salt intake recommendations for adults with OH are supported by robust evidence, informed by an appropriate risk–benefit analysis [9]. The STOOD trial will inform the feasibility of future definitive trials to address the knowledge gap for salt intake and OH.

Our trial has a number of limitations. Firstly, it is open-label. Blinding of participants is not possible for practical reasons. However, to minimise the risk of bias there will be blinded assessment of 24-h ambulatory blood pressure parameters, change in formula derived 24-h urinary sodium, and cardiovascular biomarkers. Secondly, participants in the usual care arm may receive non-study recommendations to increase salt intake. All participants will be advised not to make changes to their dietary salt intake. Participants will be advised to inform study staff if they receive a clinician recommendation to commence a high or low-salt diet. Participants who are advised to commence a high or low-salt diet for an evidence-based reason, for example heart failure, will be withdrawn from the study. The OHQ will be completed at the time of withdrawal. Thirdly, the primary efficacy outcome measure is a condition-specific questionnaire evaluating OH symptoms and the impact of these symptoms on daily life, rather than hard clinical outcomes (such as fall events) which would require longer follow-up and a larger sample size, best addressed in a future, appropriately informed, definitive trial. However, this may also be considered a strength as there are no studies measuring the effect of salt supplementation on symptoms of OH and their impact on the daily lives of patients, which has been highlighted as a priority for patients [10].

Conclusion

The STOOD trial will compare salt supplementation with usual care alone to reduce symptoms of OH, as measured by the OHQ. As recommendations for long-term increases in salt intake to high intake levels may have adverse cardiovascular consequences, it necessitates the urgent need to evaluate whether there is clinical benefits from use of high-salt intake in OH, particularly older adults. This study will generate preliminary evidence to address this gap in scientific knowledge.

Trial status

As of submitting this manuscript, the study is open for participant recruitment. We are working with protocol version 1.0, February 14th, 2024. The commencement of recruitment was July 2024, with the anticipation of completing this phase by July 2025.

Protocol amendments

The investigators will not implement any deviation from the trial protocol without review and approval from the research ethics committee, with the exception of eliminating immediate hazards to trial participants. Changes will be recorded, signed by the principal investigator and filed with the protocol. Changes will not be implemented until approval from the research ethics committee is received.

Authors’ contributions

CR, AS and MOD—study conception and protocol development, MC, RAK and RS contributed to study design, AA contributed to the development of statistical analysis plan, CR and MOD wrote the first draft of the protocol, all authors were involved in manuscript editing, CR, SMcD, CMcD and EM were responsible for day-to-day trial management, CR, AS, MC, RAK and MOD acquired funding. All authors read and approved the final manuscript.

Funding

The STOOD trial is funded by the Health Research Board (HRB) of Ireland through a Definitive Intervention and Feasibility Award [DIFA-2023-019]. The HRB had no role in the design or conduct of the trial. CR was supported by the Irish Clinical Academic Training (ICAT) Programme, the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland. The funding source had no role in the design and conduct of the study or the publication decision.

Data availability

The data that support this study, including the full protocol, are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The trial protocol received approval from the Galway University Hospitals Research Ethics Committee (Ref C.A. 3086). Written informed consent will be obtained from all participants.

Consent for publication

All authors read and approved the final version of the manuscript.

Competing interests

The authors declare that they have no competing interests.