Salt supplementation in the management of orthostatic intolerance: Vasovagal syncope and postural orthostatic tachycardia syndrome

Open AccessPublished:November 10, 2021DOI:https://doi.org/10.1016/j.autneu.2021.102906

      Abstract

      Salt supplementation is a common non-pharmacological approach to the management of recurrent orthostatic syncope or presyncope, particularly for patients with vasovagal syncope (VVS) or postural orthostatic tachycardia syndrome (POTS), although there is limited consensus on the optimal dosage, formulation and duration of treatment. Accordingly, we reviewed the evidence for the use of salt supplementation to reduce susceptibility to syncope or presyncope in patients with VVS and POTS.
      We found that short-term (~3 months) salt supplementation improves susceptibility to VVS and associated symptoms, with little effect on supine blood pressure. In patients with VVS, salt supplementation is associated with increases in plasma volume, and an increase in the time taken to provoke a syncopal event during orthostatic tolerance testing, with smaller orthostatic heart rate increases, enhanced peripheral vascular responses to orthostatic stress, and improved cerebral autoregulation. Responses were most pronounced in those with a baseline sodium excretion <170 mmol/day. Salt supplementation also improved symptoms, plasma volume, and orthostatic responses in patients with POTS.
      Salt supplementation should be considered for individuals with recurrent and troublesome episodes of VVS or POTS without cardiovascular comorbidities, particularly if their typical urinary sodium excretion is low, and their supine blood pressure is not elevated. The efficacy of the response, in terms of the improvement in subjective and objective markers of orthostatic intolerance, and any potential deleterious effect on supine blood pressure, should be routinely monitored in individuals on high salt regimes.

      Keywords

      1. Aims and scope

      Orthostatic intolerance is common (
      • Rose M.S.
      • Lou Koshman M.
      • Spreng S.
      • Sheldon R.
      The relationship between health-related quality of life and frequency of spells in patients with syncope.
      ;
      • Ganzeboom K.S.
      • Mairuhu G.
      • Reitsma J.B.
      • Linzer M.
      • Wieling W.
      • van Dijk N.
      Lifetime cumulative incidence of syncope in the general population: a study of 549 dutch subjects aged 35–60 years.
      ;
      • Deveau A.P.
      • Sheldon R.
      • Maxey C.
      • Ritchie D.
      • Doucette S.
      • Parkash R.
      Sex differences in vasovagal syncope: a post hoc analysis of the prevention of syncope trials (POST) I and II.
      ;
      • Roston T.M.
      • Tran D.T.
      • Sanatani S.
      • Sandhu R.
      • Sheldon R.
      • Kaul P.
      A population-based study of syncope in the young.
      ) and recurrent syncope (fainting) or presyncope (near-fainting) has a profound negative impact on quality of life (
      • Rose M.S.
      • Lou Koshman M.
      • Spreng S.
      • Sheldon R.
      The relationship between health-related quality of life and frequency of spells in patients with syncope.
      ;
      • van Dijk N.
      • Sprangers M.A.
      • Colman N.
      • Boer K.R.
      • Wieling W.
      • Linzer M.
      Clinical factors associated with quality of life in patients with transient loss of consciousness.
      ;
      • Anderson J.B.
      • Czosek R.J.
      • Knilans T.K.
      • Marino B.S.
      The effect of paediatric syncope on health-related quality of life.
      ;
      • Armstrong K.R.
      • De Souza A.M.
      • Sneddon P.L.
      • Potts J.E.
      • Claydon V.E.
      • Sanatani S.
      Exercise and the multidisciplinary holistic approach to adolescent dysautonomia.
      ;
      • van Dijk N.
      • Sprangers M.A.
      • Boer K.R.
      • Colman N.
      • Wieling W.
      • Linzer M.
      Quality of life within one year following presentation after transient loss of consciousness.
      ) with a substantial health care burden (
      • Casini-Raggi V.
      • Bandinelli G.
      • Lagi A.
      Vasovagal syncope in emergency room patients: analysis of a metropolitan area registry.
      ; ​
      • McCarthy F.
      • McMahon C.G.
      • Geary U.
      • Plunkett P.K.
      • Kenny R.A.
      • Cunningham C.J.
      Management of syncope in the Emergency Department: a single hospital observational case series based on the application of European Society of Cardiology Guidelines.
      ). The overall goal of this review is to provide evidence on the usefulness of salt (sodium chloride) supplementation in reducing recurrent and troublesome symptoms of orthostatic intolerance. A brief overview of salt-mediated physiological changes and plausible mechanisms for its positive clinical impact will be discussed. We also aim to provide practical suggestions to health care professionals who are taking care of these challenging and heterogeneous populations. This review will focus on two of the most common causes of orthostatic syncope and presyncope, particularly in the young (who are most likely to meet eligibility criteria for salt loading), and the two conditions for which the most data are available, vasovagal syncope (VVS) and postural orthostatic tachycardia syndrome (POTS). Definitions of these conditions are provided in Table 1. Extension of salt loading to special populations will be considered in brief. Management of patients with orthostatic intolerance due to acute reversible causes such as plasma volume depletion or dehydration can be found elsewhere (
      • Lanier J.B.
      • Mote M.B.
      • Clay E.C.
      Evaluation and management of orthostatic hypotension.
      ).
      Table 1Definitions of orthostatic intolerance and common causes of orthostatic syncope or presyncope. Definitions are given for orthostatic intolerance (
      • Low P.A.
      • Sandroni P.
      • Joyner M.
      • Shen W.-K.
      Postural tachycardia syndrome (POTS).
      ;
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Textor S.C.
      • et al.
      Postural tachycardia syndrome (POTS).
      ), vasovagal syncope (
      • Benditt D.G.
      • Gert Van Dijk J.
      • Sutton R.
      Syncope.
      ;
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ), POTS (
      • Low P.A.
      • Sandroni P.
      • Joyner M.
      • Shen W.-K.
      Postural tachycardia syndrome (POTS).
      ;
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Textor S.C.
      • et al.
      Postural tachycardia syndrome (POTS).
      ), and orthostatic hypotension (
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ;
      • Wieling W.
      • Schatz I.J.
      The consensus statement on the definition of orthostatic hypotension: a revisit after 13 years.
      ). Abbreviations: VVS, vasovagal syncope; POTS, postural orthostatic tachycardia syndrome; OH, orthostatic hypotension.
      ConditionDefinition
      Orthostatic intoleranceAn umbrella term relating to the inability to tolerate orthostatic stress, whereby symptoms or signs of presyncope or syncope occur in the upright posture that are relieved when supine. Various sub-types of orthostatic tolerance exist and are typically distinguished based on the haemodynamic changes that occur with orthostatic stress.
      Vasovagal syncope (VVS)The most common form of reflex syncope mediated by the vasovagal reflex. VVS: 1) may occur with upright posture (standing or seated) or with exposure to emotional stress, pain, or medical settings; 2) is typically characterized by diaphoresis, warmth, nausea, and pallor; 3) is typically associated with vasodepressor hypotension and/or inappropriate bradycardia; and 4) is often followed by fatigue. Typical features may be absent in older patients. VVS is often preceded by identifiable triggers and/or by a characteristic prodrome. The diagnosis is made primarily on the basis of a thorough history, physical examination, and eyewitness observation, if available.
      Postural orthostatic tachycardia syndrome (POTS)A clinical syndrome usually characterized by all of the following: 1) frequent symptoms that occur with standing (e.g. lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, exercise intolerance, and fatigue); and 2) an increase in heart rate of ≥30 bpm during a positional change from supine to standing (or ≥40 bpm in those 12–19 years of age); and 3) the absence of OH (>20 mmHg reduction in systolic or >10 mmHg reduction in diastolic blood pressure). Symptoms associated with POTS include those that occur with standing (e.g. lightheadedness, palpitations); those not associated with particular postures (e.g. bloating, nausea, diarrhea, abdominal pain); and those that are systemic (e.g. fatigue, sleep disturbance, migraine headaches). The standing heart rate is often >120 bpm.
      Orthostatic hypotension (OH)Defined as a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min of assuming an upright posture. Orthostatic hypotension may be acute or chronic, symptomatic or asymptomatic. Symptoms include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, syncope, and neck and shoulder pain or “coat-hanger pain”. Causes include dehydration or hypovolemia; autonomic nervous system disorders, and use of certain medications.

      2. Current recommendations

      Current recommendations for the management of orthostatic intolerance support salt supplementation, with a Class IC (based on expert consensus and/or small studies) recommendation (
      • Brignole M.
      • Moya A.
      • de Lange F.J.
      • et al.
      2018 ESC guidelines for the diagnosis and management of syncope.
      ), although they vary in terms of the quantity of salt recommended (6–10 g of sodium chloride, or ~100–170 mmol sodium chloride, per day) (
      • Lanier J.B.
      • Mote M.B.
      • Clay E.C.
      Evaluation and management of orthostatic hypotension.
      ;
      • Brignole M.
      • Moya A.
      • de Lange F.J.
      • et al.
      2018 ESC guidelines for the diagnosis and management of syncope.
      ;
      • Loughlin E.A.
      • Judge C.S.
      • Gorey S.E.
      • et al.
      Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis.
      ;
      • Shen W.-K.
      • Sheldon R.S.
      • Benditt D.G.
      • et al.
      2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope.
      ;
      National Institute for Health and Care Excellence (NICE)
      Orthostatic Hypotension Due to Autonomic Dysfunction: Midodrine.
      ;
      • Shibao C.
      • Lipsitz L.A.
      • Biaggioni I.
      ASH position paper: evaluation and treatment of orthostatic hypotension.
      ;
      • Lahrmann H.
      • Cortelli P.
      • Hilz M.
      • Mathias C.J.
      • Struhal W.
      • Tassinari M.
      EFNS guidelines on the diagnosis and management of orthostatic hypotension.
      ). While the recommended salt dosage for patients with recurrent syncope varies, all regimens prescribe this high salt intake in addition to the typical daily intake for the general population (3400 mg sodium per day which is equivalent to 8.5 g of sodium chloride or ~150 mmol sodium chloride per day) (
      • Jackson S.L.
      • King S.M.C.
      • Zhao L.
      • Cogswell M.E.
      Prevalence of excess sodium intake in the United States - NHANES, 2009–2012.
      ). Note that the recommended salt intake for the general population is lower than the typical intake, at 2300 mg sodium per day (equivalent to 5.75 g sodium chloride or 100 mmol sodium chloride) (
      • Jackson S.L.
      • King S.M.C.
      • Zhao L.
      • Cogswell M.E.
      Prevalence of excess sodium intake in the United States - NHANES, 2009–2012.
      ). These guidelines on salt supplementation for orthostatic intolerance have been criticized for being based on limited evidence (
      • Loughlin E.A.
      • Judge C.S.
      • Gorey S.E.
      • et al.
      Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis.
      ) although the physiologic theory underpinning the rationale for salt supplementation for patients with VVS and POTS is robust.

      3. Balancing the evidence

      When considering the use of salt supplementation for patients with orthostatic intolerance we must first consider how to evaluate and reconcile the available epidemiological and physiological data, while being cognizant of the strengths and limitations of these different types of evidence (
      • Cheshire W.P.
      Highlights in clinical autonomic neuroscience: how much salt is salubrious?.
      ;
      • Wieling W.
      • Raj S.R.
      • Thijs R.D.
      Are small observational studies sufficient evidence for a recommendation of head-up sleeping in all patients with debilitating orthostatic hypotension? MacLean and Allen revisited after 70 years.
      ;
      • Cheshire W.P.
      Salt: the paradoxical philosopher’s stone of autonomic medicine.
      ). Scientific proof of effectiveness of salt supplementation for patients with syncope or presyncope requires both physiologic theory and trial evidence to be in agreement (
      • Vandenbroucke J.P.
      • de Craen A.J.
      Alternative medicine: a “mirror image” for scientific reasoning in conventional medicine.
      ). In this review we will document the growing body of evidence from small scale physiological experiments and clinical studies that salt supplementation is efficacious i.e., it induces extracellular fluid volume expansion and improves orthostatic tolerance. However, more physiological data about salt for orthostatic intolerance are needed in older adults, those with comorbidities, and other target groups. In addition, the acute beneficial effects of salt for patients with orthostatic intolerance need to be balanced with salt as a risk factor for hypertension and cardiovascular disease with long-term use. The epidemiological data clearly support a deleterious effect of a long-term high salt diet at a population level — but these data may not apply well to the population of interest in the context of salt for young patients with syncope or presyncope due to VVS or POTS, many of whom are hypotensive, and many of whom only exploit the benefits of salt supplementation episodically, when their symptoms are most troubling. Nevertheless, data on long-term outcomes in patients with orthostatic intolerance who are salt loading are lacking. Without these data, balancing the individual risk-benefit ratio from salt supplementation will be key to successful clinical management of this condition. The available data suggest there is a strong likelihood of benefit from salt loading in young patients with VVS or POTS, with clear potential to mitigate the profound impact of untreated syncope and presyncope and associated falls on quality of life, morbidity and mortality (
      • Anderson J.B.
      • Czosek R.J.
      • Knilans T.K.
      • Marino B.S.
      The effect of paediatric syncope on health-related quality of life.
      ;
      • Armstrong K.R.
      • De Souza A.M.
      • Sneddon P.L.
      • Potts J.E.
      • Claydon V.E.
      • Sanatani S.
      Exercise and the multidisciplinary holistic approach to adolescent dysautonomia.
      ;
      • Shaw B.H.
      • Borrel D.
      • Sabbaghan K.
      • et al.
      Relationships between orthostatic hypotension, frailty, falling and mortality in elderly care home residents.
      ;
      • Shaw B.H.
      • Claydon V.E.
      The relationship between orthostatic hypotension and falling in older adults.
      ;
      • Bhatia R.
      • Kizilbash S.J.
      • Ahrens S.P.
      • et al.
      Outcomes of adolescent-onset postural orthostatic tachycardia syndrome.
      ;
      • McTate E.A.
      • Weiss K.E.
      Psychosocial dimensions and functioning in youth with postural orthostatic tachycardia syndrome.
      ;
      • Gupta V.
      • Lipsitz L.A.
      Orthostatic hypotension in the elderly: diagnosis and treatment.
      ). However, this must be balanced against the theoretical risk of increasing susceptibility to hypertension and other cardiovascular diseases (
      • Karppanen H.
      • Mervaala E.
      Sodium Intake and Hypertension.
      ;
      • Rust P.
      • Ekmekcioglu C.
      Impact of salt intake on the pathogenesis and treatment of hypertension.
      ;
      • Kruit M.C.
      • Thijs R.D.
      • Ferrari M.D.
      • Launer L.J.
      • van Buchem M.A.
      • van Dijk J.G.
      Syncope and orthostatic intolerance increase risk of brain lesions in migraineurs and controls.
      ). In this article we will review what is known, and what is not known, about the use of salt supplementation to improve orthostatic tolerance in patients with recurrent syncope or presyncope.

      4. Salt supplementation and orthostatic tolerance

      4.1 Effect of salt supplementation on orthostatic tolerance

      Salt supplementation improves orthostatic tolerance and/or symptoms of orthostatic syncope or presyncope (Fig. 1) in patients with various disorders of orthostatic intolerance including VVS (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ), POTS (
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ) (Table 2) and orthostatic hypotension (
      • Loughlin E.A.
      • Judge C.S.
      • Gorey S.E.
      • et al.
      Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis.
      ;
      • Pechère-Bertschi A.
      • Nussberger J.
      • Biollaz J.
      • et al.
      Circadian variations of renal sodium handling in patients with orthostatic hypotension.
      ), which is discussed in detail in another paper in this series (
      • Biaggioni
      Blood pressure regulation in autonomic failure by dietary sodium, blood volume and posture.
      ). Many of these studies involved predominantly relatively young participants, because of the high prevalence of VVS and POTS in the young, but the participant ages were wide ranging, from 4 to 78 years. Improvements in orthostatic tolerance were seen in as little as 2–3 days after starting oral salt supplementation (
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ). Studies using intravenous saline as the means for salt loading purport even more rapid time courses of effect, which likely reflects the plasma volume expansion due to the associated fluid load rather than the salt per se (
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ). The rapid time course of oral salt loading is compatible with the known physiology, whereby approximately 50% of an ingested salt load is retained within the first 24 h (
      • Wieling W.
      • France C.R.
      • van Dijk N.
      • Kamel H.
      • Thijs R.D.
      • Tomasulo P.
      Physiologic strategies to prevent fainting responses during or after whole blood donation.
      ). The effect size for improvements in orthostatic tolerance is large (Fig. 1A). The majority of these studies were conducted in patients with VVS using an orthostatic tolerance test consisting of combined head-upright tilting with lower body negative pressure continued to presyncope to evaluate the efficacy of salt supplementation. This test has a defined end-point and documented high reproducibility, sensitivity and specificity (
      • El-Bedawi K.
      • Hainsworth R.
      Combined head-up tilt and lower body suction: a test of orthostatic tolerance.
      ;
      • Hainsworth R.
      • el-Bedawi K.M.
      Orthostatic tolerance in patients with unexplained syncope.
      ;
      • Protheroe C.L.
      • Ravensbergen H.R.J.C.
      • Inskip J.A.
      • Claydon V.E.
      Tilt testing with combined lower body negative pressure: a “gold standard” for measuring orthostatic tolerance.
      ;
      • LeLorier P.
      • Klein G.J.
      • Krahn A.
      • Yee R.
      • Skanes A.
      • Shoemaker J.K.
      Combined head-up tilt and lower body negative pressure as an experimental model of orthostatic syncope.
      ). Using this protocol, combined analyses showed an improvement in orthostatic tolerance of +7.2 ± 1.7 min (n = 131; p < 0.00001) which is considerable during this high intensity orthostatic stress (Table 2), and sufficient to normalize orthostatic tolerance in the majority of patients. With incorporation of studies using head-upright tilting alone to determine orthostatic tolerance (
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ) the improvement in orthostatic tolerance in patients with VVS is +9.3 ± 1.5 min (n = 186; p < 0.00001) (Fig. 2A ). Other studies documented the impact on orthostatic tolerance based on whether an orthostatic stress test was considered positive or negative. Using an orthostatic stress consisting of combined tilting and nitroglycerin provocation, 66% of patients with VVS with a previous positive tilt test converted to a negative tilt test after salt supplementation (
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ), which was a higher conversion rate than those on standard care (education and tilt-training) alone (35%, n = 19, p = 0.0002). Another group examined the impact of salt supplementation on tolerance to orthostatic stress continued to presyncope using lower body negative pressure alone, reporting an approximately 60% increase in orthostatic tolerance with acute salt supplementation in patients with POTS using oral rehydration salts (ORS) (90 mmol/l NaCl) (
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ). In a cohort of 106 children with either VVS or POTS, 47% of patients converted to a negative tilt test following 6 months of salt supplementation using ORS, and this conversion rate was significantly higher than in those on standard care (education and tilt training) alone (12%, p < 0.001) (
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ).
      Fig. 1
      Fig. 1The effects of salt supplementation on orthostatic tolerance and symptoms of orthostatic intolerance. (A) In this forest plot, each study is represented by a square, with the center of the square representing the mean difference in orthostatic tolerance with salt, and the horizontal bars showing the 95% confidence intervals. The size of the square reflects the sample size of the study. Orthostatic tolerance refers to the change in the time to presyncope in minutes following salt supplementation in a graded orthostatic stress test consisting of combined head-upright tilting and lower body negative pressure (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ), or with tilt alone without additional provocation (
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ). The overall effect is indicated by the diamond symbol with the vertical dashed line reflecting the mean difference for all studies combined, and the width of the diamond indicating the 95% confidence interval of the overall effect. Note that all of these studies were conducted in patients with VVS, and many of these studies were conducted by the same research group. The salt dosage evaluated varied widely (range 26–300 mmol/day; see ) with a weighted mean dose of approximately 96 mmol/day. (B) The percentage of participants in whom symptoms improved with salt supplementation relative to those in whom symptoms were not improved. Criteria for a failure to improve included cases where the symptoms were the same as before salt, worse than before salt, or where the improvement in symptom scores did not meet a priori criteria for a clinically meaningful improvement (
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ). The salt dosage evaluated varied (range 11–300 mmol/day; see ) with a weighted mean dose of approximately 41 mmol/day. The weighted average proportion of participants with symptomatic improvement following salt supplementation was 76% in all studies combined.
      Table 2Impact of salt supplementation on orthostatic tolerance. Abbreviations: VVS, vasovagal syncope; POTS, postural orthostatic tachycardia syndrome; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, mean arterial pressure; CO, cardiac output; PV, plasma volume; TBW, total body water; OH, orthostatic hypotension; HUT, head up tilt; BRS, cardiac baroreflex sensitivity; NaCl, sodium chloride; ORS, oral rehydration salts; MCHC, mean corpuscular hemoglobin concentration; CBFv, cerebral blood flow velocity; 24 h uNa, 24-h urinary sodium excretion; BMI, body mass index; OT, orthostatic tolerance; N/A, not applicable. Data are presented as mean ± standard error.
      ArticlePopulationAge (y) [range]NDesignDosage NaClDurationSymptomsOrthostatic toleranceSecondary outcomesBlood pressure
      Adults
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      Orthostatic syncope (VVS) with low OT44 ± 1 [34–54]
      Denotes ranges estimated based on standard deviation and mean.
      21Randomised double blind, placebo controlled120 mmol/day8 weeksImproved in all who improved OT.Increased (+9 ± 1.4 min; p < 0.002).PV increased (+185 ± 43 ml; p < 0.002).

      BV increased (+291 ± 56 ml; p < 0.002).

      BRS decreased (−2 ± 0.4 ms·mmHg−1; p < 0.002).
      No change in supine SAP, DAP or MAP. Increase in HUT SAP, DAP and MAP (p < 0.01).
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ,
      • Mtinangi B.L.
      • Hainsworth R.
      Increased orthostatic tolerance following moderate exercise training in patients with unexplained syncope.
      Orthostatic syncope (VVS) with low OT43 ± 3 [16–54]6Uncontrolled interventional study120 mmol/day7 daysN/AIncreased (+4.7 ± 0.7 min; p = 0.001).PV increased (+177 ± 22 ml; p < 0.0005).

      BV increased (+200 ± 27 ml; p < 0.001).

      BRS decreased (−3.5 ± 0.4 ml; p < 0.001).
      No change in supine SAP, DAP or MAP. Increase in HUT SAP and DAP (p < 0.01).
      6Uncontrolled interventional study120 mmol/day3 daysN/AIncreased (+6.0 ± 1.2 min; p = 0.001).PV increased (+210 ± 34 ml; p < 0.01).

      BV increased (+239 ± 38 ml; p < 0.005).

      BRS decreased (−3.0 ± 0.4 ms·mmHg−1; p < 0.005).
      No change in supine SAP, DAP or MAP. Increase in HUT SAP and DAP (p < 0.01).
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      Orthostatic syncope (VVS) with low OT43 ± 2 [14–78]98Uncontrolled interventional study1.5 mmol/kg/day3 monthsN/AIncreased (+4.4 ± 0.6 min; p < 0.05).cBrS increased (+1.8 ± 0.6 ms·mmHg−1; p < 0.005).No change in supine SAP or DAP. Increase in supine MAP (+2 ± 1 mmHg; p < 0.05).
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      VVS with low OT35 ± 4 [19–53]11Uncontrolled interventional study100 mmol/day2 monthsSymptom frequency reduced (p < 0.001).Increased (+11 ± 3 min; p < 0.005).Improved orthostatic cerebral (p < 0.02) and peripheral vascular (p < 0.005) responses.No change in supine SAP, DAP or MAP.
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      POTS33 ± 3 [18–47]13Controlled interventional study1 L IV saline solution in 60 min (154 mmol)1 hImproved (informal assessment).N/AReduced orthostatic HR (p < 0.001)Supine SAP decreased (p < 0.02) with no change in DAP. Increase in orthostatic SAP (p < 0.002) but not DAP.
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      VVS43 ± 2 [36–50]
      Denotes ranges estimated based on standard deviation and mean.
      86Controlled interventional study26 mmol/day with 1500 ml water10 daysN/AIncreased (+9.0 ± 2.1 min).No change in PV.Supine MAP decreased (p < 0.05).
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      POTS35 ± 2 [23–49]14Controlled interventional study with crossover designTotal dietary intake
      Note that in this study a standardised diet was provided that comprised the intervention, whereas all other studies provide a salt supplementation in additional to the typical dietary intake.
      of 300 mmol/day and 10 mmol/day
      6 daysNo significant difference in symptoms.N/APV increased (+279 ± 82 ml; p < 0.003) and BV increased (+287 ± 99 ml; p < 0.001)

      Orthostatic HR (p < 0.002) and noradrenaline decreased (p < 0.02)
      No change in supine SAP, DAP.
      Children
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      OH14 [N/A]1Case report135-150 mmol/day48 hBoth OH and symptoms alleviated with continued NaCl treatment.Improved by 3 min.Increase TBW by ~4%, CO by 16%.Ambulatory blood pressure increase (pre: 98/59 mmHg; post: 122/73 mmHg).
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      POTS11 ± 2 [11–15]
      Denotes ranges estimated based on standard deviation and mean.
      30Controlled interventional study1.7–2.5 mmol/kg/day1 monthSymptoms improved in 51.5% of patients.N/ASymptom severity negatively correlated with baseline 24 h uNa. Salt supplementation was more effective when 24 h uNa <124 mmol/day.No change in supine SAP, DAP.
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      VVS12 ± 2 [7–17]87Controlled interventional study500 ml ORS (30 mmol/day)6 monthsSignificant improvement in recurrent syncopal episodes with ORS (p = 0.029)Improved HUT result (p = 0.0002)No difference in responses in vasodepressor and mixed syncope patientsN/A
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      POTS12 ± 3 [7–17]
      Denotes ranges estimated based on standard deviation and mean.
      54Controlled interventional study250 ml ORS (11 mmol/day)3 monthsSymptoms improved in 54% of patientsN/AIndividuals with low BMI were more likely to respond to ORSN/A
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      POTS11 ± 3 [5–16]35Controlled interventional study500 ml ORS (11 mmol/day)3 monthsSymptom scores decreased (p < 0.05)N/AChildren with lower MCV and higher MCHC were more likely to have symptomatic benefit from ORS.N/A
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      POTS20 ± 1 [15–29]10Randomised controlled trial1 L ORS (90 mmol/l) in 30 min

      1 L IV saline solution in 30 min (154 mmol)

      No fluids
      1 hN/ABoth ORS (p < 0.001) and IV saline (p < 0.05) improved LBNP tolerance compared to no fluids.Increased CBFv and CO during tilt with ORS, but not with IV saline, compared to no fluids.No change in MAP responses to LBNP with ORS or IV saline compared to no fluids.
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      VVS and POTS12 ± 3 [4–18]105Controlled interventional study500 ml ORS (30 mmol/day) ≥6 years old

      250 ml ORS (15 mmol//day) <6 years old
      6–25 monthsImproved in more (94%) of those on ORS than health education (72%) at 6 months (p < 0.003)Conversion to negative tilt test in 47% of ORS and 12% of health education (p < 0.001) at 6 monthsLong term symptom recurrence was reduced more in the ORS than health education group (p 〈0001). ORS was more efficacious in vasodepressor VVS than mixed or cardioinhibitory VVS and POTS (p = 0.035).N/A
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      VVS15 ± 212Controlled interventional study1 L IV saline solution (154 mmol) in 20 min1 hN/AIncreased 20.6 ± 2.1 min (p < 0.001). Conversion to negative test in all patients.Reduced orthostatic HR (p < 0.05).No change in SAP, DAP. Increase in orthostatic SAP (p < 0.05).
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      VVS and POTS10 ± 3 [4–16]75Controlled interventional study500 ml ORS (30 mmol/day) ≥6 years old

      250 ml ORS (15 mmol//day) <6 years old
      3–22 weeksSymptoms improved in 82% in the 36% of participants who returned for follow up.Conversion to negative tilt test in 48% of the 36% of participant who returned for follow up.24 h uNA increased from 119 ± 53 to 159 ± 73 mmol/dayN/A
      low asterisk Denotes ranges estimated based on standard deviation and mean.
      Note that in this study a standardised diet was provided that comprised the intervention, whereas all other studies provide a salt supplementation in additional to the typical dietary intake.
      Fig. 2
      Fig. 2Effect of salt supplementation on orthostatic tolerance (A), plasma volume (B), blood pressure (C) and baroreflex sensitivity (D). Data shown are pooled results from 10 studies (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ) in patients with VVS or POTS, with a combined sample size of up to 247 participants, depending on the variable examined. Each study is represented by a circle, with the center of the circle representing the study mean, and the size of the circle proportionate to the study sample size. The aggregate mean and standard error is denoted in the black squares. The salt dosage evaluated varied widely (see ) with a weighted mean dose of 84–174 mmol/day for the various outcome measures. Statistical significance is denoted for all studies combined (weighted paired Student's t-test). Abbreviations: OT, orthostatic tolerance; PV, plasma volume; SAP, systolic arterial pressure; DAP, diastolic arterial pressure, BRS, baroreflex sensitivity.
      In patients with POTS, who rarely experience frank syncope, arguably a more pertinent measure of efficacy is not orthostatic tolerance per se but rather the impact on the orthostatic tachycardia that is the hallmark feature of the condition. In one controlled interventional study that incorporated a crossover design, a dietary intervention comprising 300 mmol/day sodium (equivalent to 17.25 g salt) for 6 days blunted the orthostatic tachycardia in patients with POTS, compared to a control diet with a very low sodium content (10 mmol/day sodium or 0.575 g salt for 6 days) in the same POTS patients, and this was associated with reductions in upright plasma noradrenaline (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ). Note that while this intervention appears to be a very high salt load, it is comparable to recommendations to incorporate up to 6–10 g salt in addition to the typical dietary intake of 8.5 g salt. We analysed the impact of salt supplementation on orthostatic tachycardia in all the studies for which data were available (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects.
      ) which included data on patients with VVS (5 studies; n = 93) and POTS (3 studies; n = 27). We found that salt supplementation reduced the orthostatic heart rate increment by −11.3 ± 1.1 bpm; n = 120; p < 0.00001).
      These collective objective data highlight the beneficial effect of salt supplementation on orthostatic tolerance; however, it should be noted that many of these studies were not placebo controlled, predominantly involved young adults, and many hailed from one research group, which allows comparison between different studies with the same methodology, but may limit generalizability. Several studies reported orthostatic tolerance from responses to head-upright tilting alone, without additional provocation (
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ;
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ;
      • Benditt D.G.
      • Asso A.
      • Remole S.
      • Lurie K.
      Tilt-table testing and syncope.
      ), and the reproducibility of this modality has been questioned (
      • El-Bedawi K.
      • Hainsworth R.
      Combined head-up tilt and lower body suction: a test of orthostatic tolerance.
      ).
      Symptomatic improvements following salt supplementation included profound reductions in both the severity (
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ) and frequency (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ) of episodes (Table 2 and Fig. 1B).
      While it is clear that salt supplementation increases orthostatic tolerance and improves subjective symptoms of orthostatic syncope and presyncope in affected individuals, it is not known how long individuals should continue salt supplementation in order to gain the maximum physiological benefit, or how soon the benefits of salt supplementation are lost when salt supplementation is discontinued.

      4.2 Effects of oral rehydration salts on orthostatic tolerance

      Salt supplementation using oral rehydration salts (ORS) is reported to improve symptoms of orthostatic intolerance in children with POTS (
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ) and VVS (
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ) (Table 2). This approach to salt loading often involves very low doses of salt (11–90 mmol/day) (
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Zhang W.
      • Zou R.
      • Wu L.
      • et al.
      The changes of electrolytes in serum and urine in children with neurally mediated syncope cured by oral rehydration salts.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • Li W.
      • Wang S.
      • Liu X.
      • Zou R.
      • Tan C.
      • Wang C.
      Assessment of efficacy of oral rehydration salts in children with neurally mediated syncope of different hemodynamic patterns.
      ) and it is challenging to separate the effect of the salt load per se as opposed to the effect of improvements in hydration status from the volume load incorporated with ORS (typically 0.5–1 L). With some of the very low sodium regimes employed it is likely that the volume effect is dominant.

      4.3 Impact of intravenous saline administration on orthostatic tolerance

      Some of the available data hail from studies that used intravenous administration of 1 L of normal saline (containing 154 mmol sodium chloride) (
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ). While these studies all report high and rapid (within 1 h) efficacy of this approach, arguably it reflects direct plasma volume expansion rather than an impact of salt loading per se. Accordingly, these data may not apply well to consideration of oral salt loading in the outpatient setting. Arguably this approach is not feasible for the long-term management of patients with disorders of orthostatic intolerance, although there are reports of attempts to treat patients with medication resistant POTS with repeated intravenous hydration, with reported improvements in quality of life (
      • Moak J.P.
      • Leong D.
      • Fabian R.
      • et al.
      Intravenous hydration for management of medication-resistant orthostatic intolerance in the adolescent and young adult.
      ), but no objective measures of efficacy. Note that this approach was associated with a high rate of complications, including infection and deep vein thrombosis (18%) (
      • Moak J.P.
      • Leong D.
      • Fabian R.
      • et al.
      Intravenous hydration for management of medication-resistant orthostatic intolerance in the adolescent and young adult.
      ).

      5. Mechanisms by which salt improves orthostatic tolerance

      5.1 Expansion of plasma and blood volumes

      One key mechanism by which salt supplementation is thought to improve orthostatic tolerance is through expansion of plasma and blood volumes (Fig. 2B) (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance.
      ;
      • Wieling W.
      • Van Lieshout J.J.
      • Hainsworth R.
      Extracellular fluid volume expansion in patients with posturally related syncope.
      ). With salt loading of 120 mmol/day there is a robust and repeatable increase in plasma volume of approximately 200 ml (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance.
      ). Interestingly, these experimental data accurately recapitulate the expansion in extracellular fluid volume predicted based on known physiology (
      • Wieling W.
      • France C.R.
      • van Dijk N.
      • Kamel H.
      • Thijs R.D.
      • Tomasulo P.
      Physiologic strategies to prevent fainting responses during or after whole blood donation.
      ). This is important because individuals who are susceptible to orthostatic intolerance (both those with POTS and with VVS) have low plasma volumes (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • et al.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ), and increases in plasma volume are linearly correlated with pronounced improvements in orthostatic tolerance (Fig. 3). Indeed, expansion of plasma volume, however induced, is well documented to increase orthostatic tolerance in both patients with syncope (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Head-up sleeping improves orthostatic tolerance in patients with syncope.
      ) and healthy controls (
      • Mtinangi B.L.
      • Hainsworth R.
      Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects.
      ). Astronauts also use plasma volume expansion (by means of salt tablets and intravenous saline infusions) as a strategy to combat post-flight orthostatic intolerance (
      • Fettman M.J.
      Dietary instead of pharmacological management to counter the adverse effects of physiological adaptations to space flight.
      ;
      • Frey M.A.
      • Lathers C.
      • Davis J.
      • Fortney S.
      • Charles J.B.
      Cardiovascular responses to standing: effect of hydration.
      ;
      • Waters W.W.
      • Platts S.H.
      • Mitchell B.M.
      • Whitson P.A.
      • Meck J.V.
      Plasma volume restoration with salt tablets and water after bed rest prevents orthostatic hypotension and changes in supine hemodynamic and endocrine variables.
      ). The presumed mechanism for the expansion of plasma volume with salt loading is related to the strong influence of the sodium content on the extracellular fluid volume (including plasma volume) (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ). In individuals with low dietary sodium intake the extracellular fluid volume is low (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ), and with increases in sodium intake there is retention of sodium and water, likely involving alterations in anti-diuretic hormone secretion (
      • Armanini D.
      • Bordin L.
      • Dona' G.
      • Andrisani A.
      • Ambrosini G.
      • Sabbadin C.
      Relationship between water and salt intake, osmolality, vasopressin, and aldosterone in the regulation of blood pressure.
      ), until a new balance is achieved with higher extracellular fluid volumes, increased plasma volume, and the sodium load is excreted (
      • Armanini D.
      • Bordin L.
      • Dona' G.
      • Andrisani A.
      • Ambrosini G.
      • Sabbadin C.
      Relationship between water and salt intake, osmolality, vasopressin, and aldosterone in the regulation of blood pressure.
      ). Of note, this relationship is not linear and at high salt loads little extra volume is retained with further increases in salt intake (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Gupta B.N.
      • Linden R.J.
      • Mary D.A.
      • Weatherill D.
      The influence of high and low sodium intake on blood volume in the dog.
      ;
      • O'Connor W.J.
      Normal Renal Function: The Excretion of Water, Urea and Electrolytes Derived From Food and Drink.
      ), This is important because it explains the low efficacy of salt loading for orthostatic intolerance in individuals who already have a high sodium intake (
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ).
      Fig. 3
      Fig. 3Relationship between changes in plasma volume and changes in orthostatic tolerance. Increases in plasma volume, however they are provoked, are associated with increases in orthostatic tolerance. Salt data shown are pooled responses from five salt loading experiments that used the same protocol to determine orthostatic tolerance (head-upright tilting combined with graded lower body negative pressure continued to presyncope) in patients with VVS. Plasma volume expansion was achieved with salt loading (120 mmol/day), head-up sleeping and exercise training (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Head-up sleeping improves orthostatic tolerance in patients with syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Increased orthostatic tolerance following moderate exercise training in patients with unexplained syncope.
      ).
      Expansion of plasma volume is associated with activation of the kidney critmeter (a region at the tip of the juxtamedullary region of the cortical labyrinth in the kidney, where erythropoietin is produced) (
      • Donnelly S.
      Why is erythropoietin made in the kidney? The kidney functions as a critmeter.
      ). In consequence, erythropoietin production is increased, resulting in increased red blood cell production and thus an increase in blood volume. As noted, with salt loading of 120 mmol/day plasma volume increases by approximately 200 ml (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ). This plasma volume expansion occurs fairly rapidly (within days) (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ) and over time is accompanied by further blood volume expansion. For example, in patients with VVS, 8 weeks of a 120 mmol/day salt diet increased blood volume by approximately 300 ml (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ). In POTS patients, a 300 mmol/day sodium diet for 1 week, compared to a very low sodium diet (10 mmol/day), also increased blood volume by almost 300 ml (
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ). This is important because increases in blood volume, haematocrit and packed cell volume are also associated with improved orthostatic tolerance independent of plasma volume expansion (
      • Claydon V.E.
      • Norcliffe L.J.
      • Moore J.P.
      • et al.
      Orthostatic tolerance and blood volumes in Andean high altitude dwellers.
      ).

      5.2 Enhanced orthostatic vascular resistance responses

      Orthostatic tolerance is positively associated with the magnitude of the forearm vascular resistance (FVR) response to orthostatic stress (
      • Claydon V.E.
      • Hainsworth R.
      Increased postural sway in control subjects with poor orthostatic tolerance.
      ) (Fig. 4A ), and vasoconstrictor responses to orthostatic stress are impaired in patients with orthostatic syncope (VVS and POTS) (
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ;
      • Brown C.
      • Hainsworth R.
      Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope.
      ) (Fig. 4B). Salt supplementation enhances orthostatic vascular resistance responses in patients with VVS (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ) (Fig. 4C), restoring them to similar levels to those reported in healthy controls (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ). The magnitude of this enhancement is profound, and may contribute to the enhanced orthostatic tolerance following salt supplementation (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ). Indeed, following salt supplementation patients with VVS experienced a significantly higher maximum FVR (expressed as a percentage change from supine level) during head up tilt testing (+135.2% ± 23.9% compared with +64.4% ± 13.7% at baseline, p < 0.005) (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ) (Fig. 4C). The enhancement in vasoconstriction may reduce the reliance on orthostatic tachycardia, providing a mechanism for the reduced orthostatic heart rate increment with salt loading (
      • Loughlin E.A.
      • Judge C.S.
      • Gorey S.E.
      • et al.
      Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis.
      ). Whether orthostatic vascular responses are also enhanced with salt loading in patients with POTS is unclear.
      Fig. 4
      Fig. 4Effect of salt supplementation on vascular resistance responses. (A) The magnitude of the vasoconstriction induced during orthostatic stress is positively correlated with orthostatic tolerance in patients with vasovagal syncope (VVS) (
      • Claydon V.E.
      • Hainsworth R.
      Increased postural sway in control subjects with poor orthostatic tolerance.
      ;
      • Brown C.
      • Hainsworth R.
      Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope.
      ). (B) Patients with VVS and postural orthostatic tachycardia syndrome (POTS) have impaired vascular resistance responses to orthostatic stress compared to healthy controls (* denotes p < 0.05) (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Brown C.
      • Hainsworth R.
      Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope.
      ;
      • Claydon V.E.
      • Hainsworth R.
      Postural sway in patients with syncope and poor orthostatic tolerance.
      ). (C) Salt supplementation (100 mmol/day) enhances vasoconstrictor responses to orthostatic stress in patients with VVS (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ). Vascular resistance responses are expressed as the maximum percentage change in vascular resistance relative to the supine baseline during a graded orthostatic challenge (head-upright tilting with combined lower body negative pressure continued until presyncope).
      The mechanism for this enhanced vascular response to orthostatic stress is unclear. One possibility is that there is a direct effect on reflex control at the level of the vasculature. This is supported by animal experiments in which salt loading enhanced vasoconstrictor responses in isolated vessels to applied noradrenaline (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Hainsworth R.
      • Drinkhill M.J.
      Cardiovascular adjustments for life at high altitude.
      ;
      • Hainsworth R.
      • Sofola O.A.
      • Knill A.J.P.
      • Drinkhill M.J.
      Influence of dietary salt intake on the response of isolated perfused mesenteric veins of the dog to vasoactive agents.
      ), and blunted the local vasodilatory responses to leptin (
      • Jaffar M.M.
      • Myers D.S.
      • Hainsworth L.J.
      • Hainsworth R.
      • Drinkhill M.J.
      Effects of dietary salt loading on the responses of isolated rat mesenteric arteries to leptin.
      ) and acetylcholine (
      • Hainsworth R.
      • Sofola O.A.
      • Knill A.J.P.
      • Drinkhill M.J.
      Influence of dietary salt intake on the response of isolated perfused mesenteric veins of the dog to vasoactive agents.
      ). Another possibility is that salt supplementation enhances baroreflex sensitivity, indirectly promoting enhanced vascular responses, although evidence for this effect in human physiology is contradictory (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects.
      ).
      Interestingly, one study examined the impact of short-term (6 days) salt supplementation on endothelial function in patients with POTS, and found no evidence of a detrimental effect (
      • Smith E.C.
      • Celedonio J.
      • Nwazue V.C.
      High-sodium diet does not worsen endothelial function in female patients with postural tachycardia syndrome.
      ) suggesting that the enhanced reflex vasoconstriction does not come at the cost of impaired vasodilatation.

      5.3 Improved control of cerebral blood flow

      The enhancement of vascular responses to orthostatic stress following salt supplementation may not be restricted to the peripheral vasculature. There is also evidence that salt supplementation enhances cerebral vascular responses (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ) with less dependence of cerebral blood flow on perfusion pressure (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ) in patients with VVS. Some studies have found that in individuals with VVS regulation of cerebral blood flow is impaired, with strong dependence of cerebral blood flow on perfusion pressure, and little ability to buffer changes in blood pressure (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ). With salt supplementation this impairment in cerebral autoregulation is reversed (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ), with restoration of responses to levels similar to those reported in healthy controls (
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ;
      • Claydon V.E.
      • Schroeder C.
      • Norcliffe L.J.
      • Jordan J.
      • Hainsworth R.
      Water drinking improves orthostatic tolerance in patients with posturally related syncope.
      ;
      • Schroeder C.
      • Bush V.E.
      • Norcliffe L.J.
      • et al.
      Water drinking acutely improves orthostatic tolerance in healthy subjects.
      ). The mechanism for the enhancement in cerebral vascular control with salt supplementation in patients with VVS is not known, and may reflect a direct effect of sodium on the cerebral vessels, or an indirect effect of the enhanced orthostatic cardiovascular stability and increased peripheral vascular responses reducing the extent to which cerebral autoregulation is challenged by orthostatic stress. The effect of salt supplementation on cerebral vascular responses in patients with POTS has not yet been assessed.

      5.4 Effects on sympathetic outflow

      The impact of salt supplementation on basal sympathetic drive and vascular tone is unclear. There is a lack of significant impact of salt supplementation on supine diastolic blood pressure in patients with orthostatic intolerance (Fig. 2C), and this is one proxy for global vascular tone. This suggests one of three possibilities. First, basal sympathetic tone may not be increased; second, basal sympathetic tone may be increased in some vascular beds but not others; or finally, basal sympathetic tone may be increased but compensated by reductions in vascular tone that are mediated via other mechanisms. These issues are particularly challenging to tease apart because there is a paucity of data on the effects of salt supplementation on the peripheral vasculature, and because patients with orthostatic disorders are known to regulate blood vessel tone differently to individuals with normal orthostatic tolerance (
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ;
      • Brown C.
      • Hainsworth R.
      Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope.
      ;
      • Lambert E.
      • Lambert G.
      Sympathetic dysfunction in vasovagal syncope and the postural orthostatic tachycardia syndrome.
      ;
      • Gulli G.
      • Cooper V.L.
      • Claydon V.E.
      • Hainsworth R.
      Prolonged latency in the baroreflex mediated vascular resistance response in subjects with postural related syncope.
      ). There are reports of increased basal muscle sympathetic nerve activity in individuals with normal orthostatic tolerance exposed to high salt diets, particularly those with salt sensitive responses (
      • Yatabe M.S.
      • Yatabe J.
      • Yoneda M.
      ;
      • Strazzullo P.
      • Barbato A.
      • Vuotto P.
      • Galletti F.
      Relationships between salt sensitivity of blood pressure and sympathetic nervous system activity: a short review of evidence.
      ;
      • Sztajzel J.
      • Golay A.
      • Makoundou V.
      • et al.
      Impact of body fat mass extent on cardiac autonomic alterations in women.
      ;
      • Chen J.
      • Gu D.
      • Huang J.
      • et al.
      Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study.
      ), with increases in renal nerve activity (
      • Sripairojthikoon W.
      • Oparil S.
      • Wyss J.M.
      Renal nerve contribution to NaCl-exacerbated hypertension in spontaneously hypertensive rats.
      ), diminished central sympathetic inhibition (
      • Chen Y.F.
      • Meng Q.C.
      • Wyss J.M.
      • Jin H.
      • Oparil S.
      High NaCl diet reduces hypothalamic norepinephrine turnover in hypertensive rats.
      ;
      • Oparil S.
      • Yang R.H.
      • Jin H.K.
      • Wyss J.M.
      • Chen Y.F.
      Central mechanisms of hypertension.
      ) and elevated plasma and urinary noradrenaline levels reported in salt-sensitive hypertensive rats (
      • Winternitz S.R.
      • Oparil S.
      Sodium-neural interactions in the development of spontaneous hypertension.
      ). Whether basal sympathetic activity is increased in patients with orthostatic intolerance who are salt loading, and if so, whether this is compensated through some other mechanism(s) is not known.

      5.5 Effects on baroreflex sensitivity

      The arterial baroreflex is a key mechanism for buffering orthostatic changes in blood pressure (
      • Hainsworth R.
      • Claydon V.E.
      Syncope and fainting.
      ) and increases in orthostatic baroreflex regulation of vascular resistance responses are associated with increases in orthostatic tolerance (
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ). Despite hypothesized involvement of modification of baroreflex function with salt supplementation, our combined analyses of the available data showed no significant effect of salt supplementation on cardiac baroreflex sensitivity in patients with VVS (Fig. 2D). Of note, there are no data on the impact of salt loading on baroreflex sensitivity in patients with POTS. The overall lack of effect of salt supplementation on baroreflex sensitivity in patients with VVS is in keeping with the conflicting reports in this area, with some studies reporting increases in baroreflex sensitivity with salt loading (
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ) and some reporting decreases (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ). This likely reflects the opposing direct and indirect effects of salt on baroreflex function. Increases in plasma volume are indirectly associated with decreases in baroreflex sensitivity (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Vatner S.F.
      • Boettcher D.H.
      • Heyndrickx G.R.
      • McRitchie R.J.
      Reduced baroreflex sensitivity with volume loading in conscious dogs.
      ;
      • Billman G.E.
      • Dickey D.T.
      • Teoh K.K.
      • Stone H.L.
      Effects of central venous blood volume shifts on arterial baroreflex control of heart rate.
      ), possibly secondary to activation of intrathoracic receptors that regulate baroreflex function (
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Victor R.G.
      • Mark A.L.
      Interaction of cardiopulmonary and carotid baroreflex control of vascular resistance in humans.
      ;
      • Pawelczyk J.A.
      • Raven P.B.
      Reductions in central venous pressure improve carotid baroreflex responses in conscious men.
      ;
      • Hainsworth R.
      Reflexes from the heart.
      ). Conversely, the direct effect of salt supplementation appears to be to increase baroreflex sensitivity (
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ). There is some experimental evidence in support of this in animal models, whereby reductions in sodium intake were associated with decreased baroreflex sensitivity and vice versa (;
      • Kunze D.L.
      • Brown A.M.
      Sodium sensitivity of baroreceptors. Reflex effects on blood pressure and fluid volume in the cat.
      ;
      • Echtenkamp S.F.
      • Anderson A.C.
      Baroreflex modulation by cardiopulmonary receptors during chronic sodium depletion.
      ). Similarly, in healthy adults, salt supplementation has been shown to increase cardiac vagal baroreflex sensitivity (
      • Babcock M.C.
      • Brian M.S.
      • Watso J.C.
      • et al.
      Alterations in dietary sodium intake affect cardiovagal baroreflex sensitivity.
      ).
      Crucially, none of the available data in humans considered baroreflex resetting, and all examined only the cardiac arm of the baroreflex response — arguably the more important variable in the context of orthostatic tolerance and salt supplementation is the impact of salt supplementation on vascular resistance responses (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Effects of moderate exercise training on plasma volume, baroreceptor sensitivity and orthostatic tolerance in healthy subjects.
      ). There are no data on the impact of salt loading on vascular baroreflex sensitivity in patients with orthostatic intolerance, but as noted previously, there are reports that salt loading improves orthostatic vasoconstriction in patients with VVS, contributing to the improvements in orthostatic tolerance observed (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ). Certainly, these data fit with evidence that, regardless of basal sympathetic tone, there is a salt-induced increased vascular responsiveness to further sympathetic stimulation (
      • Bragulat E.
      • de la Sierra A.
      • Antonio M.T.
      • Coca A.
      Endothelial dysfunction in salt-sensitive essential hypertension.
      ).

      6. Effect of salt supplementation on supine blood pressure

      6.1 Salt supplementation has a minimal effect on supine blood pressure in patients with VVS and POTS

      In the general population, life-long high salt intake is associated with an increased risk of hypertension (
      • Karppanen H.
      • Mervaala E.
      Sodium Intake and Hypertension.
      ). High dietary salt intake is also a major risk factor for stroke and other cardiovascular pathologies (
      • Rust P.
      • Ekmekcioglu C.
      Impact of salt intake on the pathogenesis and treatment of hypertension.
      ), and may impair bone mineral content and density (
      • Robinson A.T.
      • Edwards D.G.
      • Farquhar W.B.
      The influence of dietary salt beyond blood pressure.
      ) and promote inflammation (
      • Zhou X.
      • Zhang L.
      • Ji W.-J.
      • et al.
      Variation in dietary salt intake induces coordinated dynamics of monocyte subsets and monocyte-platelet aggregates in humans: implications in end organ inflammation.
      ;
      • Yi B.
      • Titze J.
      • Rykova M.
      • et al.
      Effects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: a longitudinal study.
      ). In young individuals with normal orthostatic tolerance high salt intake may even have a programming effect, whereby blood pressure remains elevated even after a high salt intake has been reduced (
      • Frisoli T.M.
      • Schmieder R.E.
      • Grodzicki T.
      • Messerli F.H.
      Salt and hypertension: is salt dietary reduction worth the effort?.
      ). While these trends are well-described in the population at large, for whom hypertension is a growing concern, whether this occurs in patients with orthostatic intolerance, and what duration and dosage of high salt intake might elicit a programming effect if it does occur is not known (
      • Pechère-Bertschi A.
      • Nussberger J.
      • Biollaz J.
      • et al.
      Circadian variations of renal sodium handling in patients with orthostatic hypotension.
      ).
      We performed a combined analysis of the available data examining the impact of relatively prolonged salt supplementation on blood pressure in patients with recurrent orthostatic syncope or presyncope (VVS or POTS) (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Garland E.M.
      • Gamboa A.
      • Nwazue V.C.
      • et al.
      Effect of high dietary sodium intake in patients with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Bellard E.
      • Fortrat J.O.
      • Custaud M.A.
      • Victor J.
      • Greenleaf J.
      • Lefthériotis G.
      Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.
      ). These analyses showed no significant effect of high salt intake on supine diastolic (DAP: +0.3 ± 0.5 mmHg; n = 247; p = 0.618) or mean (MAP: −0.9 ± 0.4 mmHg; n = 152; p = 0.523) arterial pressures (Fig. 2C and Table 1) following salt supplementation for durations of up to three months. We did, however, see a small but statistically significant increase in systolic arterial pressure (SAP: +1.7 ± 0.7 mmHg; n = 247; p = 0.014). Note that blood pressures both before (109 ± 0.7 / 66 ± 0.5 mmHg, n = 247) and after salt supplementation (111 ± 1.7 / 66 ± 0.6 mmHg, n = 247) were well below established cutoffs for cardiovascular risk (
      • Virani S.S.
      • Alonso A.
      • Benjamin E.J.
      • et al.
      ), suggesting that, at least in this cohort of patients with orthostatic intolerance, any impact of salt supplementation on blood pressure is not clinically meaningful, at least in the short term (months).
      Another way to consider the theoretical risk of hypertension in patients with orthostatic intolerance who salt load is to consider the incidence of salt sensitivity (defined as a parallel change in blood pressure in response to a change in salt intake).
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      showed that while 70% of individuals experienced increases in orthostatic tolerance with salt supplementation, only 31% met their criteria of being salt sensitive (defined as an increase in MAP greater than 5 mmHg following salt supplementation). Similarly,
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      found that while 80% of participants had increases in orthostatic tolerance that brought them within a “normal” range, only 18% had salt-sensitive blood pressure responses. While cut-offs for salt sensitivity can vary (
      • Elijovich F.
      • Weinberger M.H.
      • CAM Anderson
      Salt sensitivity of blood pressure: a scientific statement from the American Heart Association.
      ), the definition of salt sensitivity as >5 mmHg rise in blood pressure with salt loading in these studies is considerably more conservative than the commonly used definition of >10 mmHg (
      • Elijovich F.
      • Weinberger M.H.
      • CAM Anderson
      Salt sensitivity of blood pressure: a scientific statement from the American Heart Association.
      ) and many of these individuals identified as salt sensitive based on the change in blood pressure following salt supplementation still had blood pressure values far below current guidelines for hypertension. Thus, while salt sensitivity is a well-documented phenomenon, it is not clear whether it is a trait that is exhibited strongly by individuals with orthostatic intolerance, in whom low plasma volumes (
      • El-Sayed H.
      • Hainsworth R.
      Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance.
      ), impaired vasoconstrictor responses (
      • Claydon V.E.
      • Hainsworth R.
      Increased postural sway in control subjects with poor orthostatic tolerance.
      ;
      • Bush V.E.
      • Wight V.L.
      • Brown C.M.
      • Hainsworth R.
      Vascular responses to orthostatic stress in patients with postural tachycardia syndrome (POTS), in patients with low orthostatic tolerance, and in asymptomatic controls.
      ;
      • Brown C.
      • Hainsworth R.
      Forearm vascular responses during orthostatic stress in control subjects and patients with posturally related syncope.
      ), and hypotensive responses (at least when upright) (
      • van Dijk J.G.
      ) are dominant. In addition, most studies of salt sensitivity have focused on individuals with a long term or even lifelong high salt intake, whereas most individuals with orthostatic intolerance who salt load do this for relatively short time periods (months-years) while their symptoms are most troublesome.
      It should be noted, however, that although supine blood pressures were little affected by salt loading over several months, salt supplementation may cause rebalancing of the complex physiological mechanisms responsible for blood pressure regulation, and the long term effects of this are unclear. Any risks associated with salt supplementation must be balanced against the known severe impact of disorders of orthostatic intolerance on quality of life (
      • Anderson J.B.
      • Czosek R.J.
      • Knilans T.K.
      • Marino B.S.
      The effect of paediatric syncope on health-related quality of life.
      ;
      • Armstrong K.R.
      • De Souza A.M.
      • Sneddon P.L.
      • Potts J.E.
      • Claydon V.E.
      • Sanatani S.
      Exercise and the multidisciplinary holistic approach to adolescent dysautonomia.
      ;
      • Bhatia R.
      • Kizilbash S.J.
      • Ahrens S.P.
      • et al.
      Outcomes of adolescent-onset postural orthostatic tachycardia syndrome.
      ;
      • McTate E.A.
      • Weiss K.E.
      Psychosocial dimensions and functioning in youth with postural orthostatic tachycardia syndrome.
      ), falls and associated injuries (
      • Shaw B.H.
      • Borrel D.
      • Sabbaghan K.
      • et al.
      Relationships between orthostatic hypotension, frailty, falling and mortality in elderly care home residents.
      ;
      • Shaw B.H.
      • Claydon V.E.
      The relationship between orthostatic hypotension and falling in older adults.
      ), and cardiovascular morbidity (
      • Gupta V.
      • Lipsitz L.A.
      Orthostatic hypotension in the elderly: diagnosis and treatment.
      ).
      One factor that might complicate the interpretation of the impact of salt supplementation on blood pressure in patients with orthostatic intolerance is the known significant increase in upright blood pressure following salt supplementation in this population (
      • Loughlin E.A.
      • Judge C.S.
      • Gorey S.E.
      • et al.
      Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • et al.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Burklow T.R.
      • Moak J.P.
      • Bailey J.J.
      • Makhlouf F.T.
      Neurally mediated cardiac syncope: autonomic modulation after normal saline infusion.
      ). This, of course, is the desired effect of the therapy in these individuals with orthostatic intolerance. The ideal therapy will improve blood pressure on sitting/standing, but not while supine. The supine blood pressure, therefore, is a better indicator of any potential deleterious effects of salt supplementation on blood pressure in this population. If necessary, 24-hour blood pressure monitoring can be considered to fully evaluate any impact of salt supplementation on blood pressure regulation in patients with orthostatic intolerance. To date, the effects of salt supplementation on diurnal blood pressures in patients with VVS and POTS are not known, but there is one report in patients with orthostatic hypotension in whom nocturnal blood pressures were found to not be affected after one week of consuming a high salt (6 g sodium chloride per day) diet (
      • Pechère-Bertschi A.
      • Nussberger J.
      • Biollaz J.
      • et al.
      Circadian variations of renal sodium handling in patients with orthostatic hypotension.
      ).
      While the long-term effects of salt supplementation in patients with orthostatic intolerance have not been assessed, current evidence suggests that there is a very low risk of developing significant hypertension, and high likelihood of symptomatic benefit, of salt supplementation for 3–6 months in patients with uncomplicated syncope or presyncope (VVS and POTS) with low supine blood pressure and low typical dietary salt intake (Table 1 and Fig. 2). Further research is needed to examine whether these individuals have a higher incidence of developing significant hypertension or end organ damage with longer durations of salt supplementation or in later life.

      7. Salt supplementation in special populations

      7.1 Salt supplementation in those with high salt intake and/or hypertension

      The benefits of salt supplementation for the prevention of recurrent syncope and presyncope are most prominent in patients with low supine blood pressure, and low urinary sodium excretion (and therefore low dietary sodium intake) prior to intervention (
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ). This is to be expected, as the potential for a ceiling effect in those who already have a high salt intake, and will not experience benefit from further increases in salt intake, is reduced (
      • Gupta B.N.
      • Linden R.J.
      • Mary D.A.
      • Weatherill D.
      The influence of high and low sodium intake on blood volume in the dog.
      ;
      • O'Connor W.J.
      Normal Renal Function: The Excretion of Water, Urea and Electrolytes Derived From Food and Drink.
      ). Not only are they less likely to experience benefit from salt loading, but individuals with higher baseline urinary sodium excretion are also more likely to exhibit increases in supine blood pressure following further increases in salt intake (
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance.
      ). Based on the available data, it seems prudent to avoid salt supplementation in adults with a 24-h urinary sodium excretion >170 mmol (
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance.
      ), and in children with a 24-h urinary sodium excretion >124 mmol/day (
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ), particularly if this is associated with high supine blood pressure.

      7.2 Sex differences in responses to salt supplementation

      When considering salt supplementation for the treatment of orthostatic intolerance, it is important to consider whether the risk:benefit ratio for initiating salt supplementation might be affected by participant sex. Most studies examining salt loading for orthostatic intolerance have had a bias towards female participants (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ), and this is not surprising considering the known higher susceptibility to orthostatic intolerance in females than males (
      • Deveau A.P.
      • Sheldon R.
      • Maxey C.
      • Ritchie D.
      • Doucette S.
      • Parkash R.
      Sex differences in vasovagal syncope: a post hoc analysis of the prevention of syncope trials (POST) I and II.
      ;
      • Protheroe C.L.
      • Ravensbergen H.R.J.C.
      • Inskip J.A.
      • Claydon V.E.
      Tilt testing with combined lower body negative pressure: a “gold standard” for measuring orthostatic tolerance.
      ;
      • Hainsworth R.
      • Claydon V.E.
      Syncope and fainting.
      ;
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome–current experience and concepts.
      ;
      • Ruwald M.H.
      • Hansen M.L.
      • Lamberts M.
      • et al.
      The relation between age, sex, comorbidity, and pharmacotherapy and the risk of syncope: a danish nationwide study.
      ). However, women (particularly premenopausal women who have the highest incidence of syncopal events) (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • He J.
      • Gu D.
      • Chen J.
      • et al.
      Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study.
      ) are known to have different peripheral vascular control to men (
      • Eisenach J.H.
      • Clark E.S.
      • Charkoudian N.
      • et al.
      Effects of chronic sympathectomy on vascular function in the human forearm.
      ;
      • Ferrer M.
      • Meyer M.
      • Osol G.
      Estrogen replacement increases beta-adrenoceptor-mediated relaxation of rat mesenteric arteries.
      ;
      • Hart E.C.
      • Charkoudian N.
      • Wallin B.G.
      • Curry T.B.
      • Eisenach J.
      • Joyner M.J.
      Sex and ageing differences in resting arterial pressure regulation: the role of the beta-adrenergic receptors.
      ;
      • Molinari C.
      • Battaglia A.
      • Grossini E.
      • Mary D.A.
      • Surico N.
      • Vacca G.
      The role of beta 2-adrenergic vascular receptors in the peripheral vasodilation caused by 17 beta-estradiol in anesthetized pigs.
      ;
      • Joyner M.J.
      • Barnes J.N.
      • Hart E.C.
      • Wallin B.G.
      • Charkoudian N.
      Neural control of the circulation: how sex and age differences interact in humans.
      ), with lower plasma volumes (even after normalisation for body surface area) (
      • Hurley P.J.
      Red cell and plasma volumes in normal adults.
      ), lower blood pressures, and impaired orthostatic vasoconstrictor responses (
      • National Center for Health Statistics (US). Health, United Statescollab
      ;
      • Ali Y.S.
      • Daamen N.
      • Jacob G.
      • et al.
      Orthostatic intolerance: a disorder of young women.
      ;
      • Fu Q.
      • Arbab-Zadeh A.
      • Perhonen M.A.
      • Zhang R.
      • Zuckerman J.H.
      • Levine B.D.
      Hemodynamics of orthostatic intolerance: implications for gender differences.
      ;
      • Ganzeboom K.S.
      • Colman N.
      • Reitsma J.B.
      • Shen W.K.
      • Wieling W.
      Prevalence and triggers of syncope in medical students.
      ). This might make them more likely to have a favorable orthostatic response to salt loading than men, although data on any sex differences in orthostatic tolerance in the context of responses to salt loading are currently lacking. There are also reports that women are more susceptible to the hypertensive effects of salt supplementation (
      • Elijovich F.
      • Weinberger M.H.
      • CAM Anderson
      Salt sensitivity of blood pressure: a scientific statement from the American Heart Association.
      ;
      • He J.
      • Gu D.
      • Chen J.
      • et al.
      Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study.
      ), and this should be kept in mind when considering salt supplementation in females. There are no data on the safety or efficacy of salt supplementation in pregnant females with recurrent syncope or presyncope.

      7.3 Racial differences in responses to salt supplementation

      In terms of race, Black people appear to have a higher orthostatic tolerance compared to White people (
      • Ahmed J.
      • Deeprasertkul P.
      • Monahan K.M.
      • LeLorier P.
      Racial differences in response to tilt-table testing in patients refered.
      ;
      • Kumba H.
      • Stachenfeld N.
      Greater orthostatic tolerance in young black compared with white women.
      ), and are less likely to experience syncope based on population studies (
      • Kumba H.
      • Stachenfeld N.
      Greater orthostatic tolerance in young black compared with white women.
      ;
      • Bastani A.
      • Su E.
      • Adler D.H.
      • et al.
      Comparison of 30-day serious adverse clinical events for elderly patients presenting to the emergency department with near-syncope versus syncope.
      ), as well as data on blood donation syncopal reactions (
      • Newman B.H.
      Vasovagal reactions in high school students: findings relative to race, risk factor synergism, female sex, and non-high school participants.
      ;
      • van den Berg K.
      • Lam J.
      • Bruhn R.
      • Custer B.
      • Murphy E.L.
      Water administration and the risk of syncope and presyncope during blood donation: a randomized clinical trial.
      ;
      • Wiltbank T.B.
      • Giordano G.F.
      • Kamel H.
      • Tomasulo P.
      • Custer B.
      Faint and prefaint reactions in whole-blood donors: an analysis of predonation measurements and their predictive value.
      ), with more rapid increases in blood pressure and heart rate during prolonged standing (
      • Goldstein I.B.
      • Shapiro D.
      The cardiovascular response to postural change as a function of race.
      ). The underlying mechanisms and relative contribution of genetic or environmental factors to the greater susceptibility to syncope in White people have yet to be elucidated. Most of the studies on salt supplementation for the improvement of orthostatic tolerance have not provided information on participant race, and no study to date has examined whether the efficacy of salt supplementation for improvement of orthostatic tolerance is related to race. However, it is well known that Black people are more likely to exhibit salt-sensitivity (
      • Weinberger M.H.
      • Luft F.C.
      • Bloch R.
      • et al.
      The blood pressure-raising effects of high dietary sodium intake: racial differences and the role of potassium.
      ;
      • RCJ Morris
      • Sebastian A.
      • Forman A.
      • Tanaka M.
      • Schmidlin O.
      Normotensive salt sensitivity: effects of race and dietary potassium.
      ;
      • Vollmer W.M.
      • Sacks F.M.
      • Ard J.
      • et al.
      Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASH-sodium trial.
      ). The risk of a hypertensive response to salt loading in people of Asian descent is not clear — their blood pressure is reported to decrease with reductions in salt intake (
      • He J.
      • Gu D.
      • Chen J.
      • et al.
      Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study.
      ), but whether the inverse is true is less clear. Data on other ethnicities are lacking, particularly in the context of salt loading for syncope.

      7.4 Salt supplementation in the elderly and individuals with other comorbid conditions

      There are no data on the safety and efficacy of salt supplementation for orthostatic disorders in individuals with other comorbid conditions for which sodium or fluid restrictions apply. At the present time it seems prudent to avoid salt supplementation in individuals with cardiovascular or renal conditions that might be exacerbated by salt loading or more likely to precipitate hypertensive responses to high salt intake. Of note, obese individuals are more likely to experience a hypertensive response to salt loading (
      • He J.
      • Gu D.
      • Chen J.
      • et al.
      Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study.
      ). There are limited data on salt supplementation in older adults and most studies to date have focused on young individuals who typically experience VVS or POTS, and where older adults were studied, data were not analysed with age as a confound (Table 2). Whether older adults with orthostatic intolerance experience the same benefit from salt loading as young individuals is not clear, particularly given that VVS and POTS are less common causes of syncope and presyncope in older adults (
      • Sheldon R.S.
      • Grubb II, B.P.
      • Olshansky B.
      • et al.
      2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ;
      • Ungar A.
      • Mussi C.
      • Del Rosso A.
      • et al.
      Diagnosis and characteristics of syncope in older patients referred to geriatric departments.
      ;
      • Del Rosso A.
      • Alboni P.
      • Brignole M.
      • Menozzi C.
      • Raviele A.
      Relation of clinical presentation of syncope to the age of patients.
      ). It is also unclear whether older adults, who in general have a higher susceptibility to hypertension and cardiovascular disease (
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      Heart disease and stroke statistics–2013 update: a report from the American Heart Association.
      ) and are more likely to exhibit salt-sensitivity (
      • Elijovich F.
      • Weinberger M.H.
      • CAM Anderson
      Salt sensitivity of blood pressure: a scientific statement from the American Heart Association.
      ;
      • Weinberger M.H.
      • Fineberg N.S.
      Sodium and volume sensitivity of blood pressure. Age and pressure change over time.
      ), are more prone to the potential detrimental effects of salt supplementation. Only one study examined the effect of age on the blood pressure response to salt loading (3 months) in patients with syncope, and found no significant relationship (n = 98, age range 14–78 years) (
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ). Of note, in order to qualify for salt loading the participants in this study had documented poor orthostatic tolerance, low urinary sodium excretion and normotensive supine blood pressures and so were at a lower risk for the development of salt-induced hypertension. Salt supplementation in older adults with syncope or presyncope secondary to neurogenic orthostatic hypertension is often complicated by supine hypertension and is discussed further in another paper in this series (
      • Biaggioni
      Blood pressure regulation in autonomic failure by dietary sodium, blood volume and posture.
      ).

      8. Strategies for salt supplementation

      There is limited evidence on the optimum dosage, formulation and duration of salt supplementation for patients with orthostatic syncope or presyncope and this complicates the interpretation of the available trials data. Here we consider strategies for oral salt loading because of the limited practicality and high risk of intravenous approaches for community dwelling patients with syncope. A wide variety of different regimes have been adopted ranging from 11 to 300 mmol/day sodium chloride (Table 1) (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Chu W.
      • Wang C.
      • Wu L.
      • Lin P.
      • Li F.
      • Zou R.
      Oral rehydration salts: an effective choice for the treatment of children with vasovagal syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • Lu W.
      • Yan H.
      • Wu S.
      • Xu W.
      • Jin H.
      • Du J.
      Hemocytometric measures predict the efficacy of oral rehydration for children with postural tachycardia syndrome.
      ;
      • Medow M.S.
      • Guber K.
      • Chokshi S.
      • Terilli C.
      • Visintainer P.
      • Stewart J.M.
      The benefits of oral rehydration on orthostatic intolerance in children with postural tachycardia syndrome.
      ;
      • Li H.
      • Wang Y.
      • Liu P.
      • et al.
      Body mass index (BMI) is associated with the therapeutic response to oral rehydration solution in children with postural tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.
      ;
      • Mtinangi B.L.
      • Hainsworth R.
      Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope.
      ;
      • Cooper V.L.
      • Hainsworth R.
      Effects of dietary salt on orthostatic tolerance, blood pressure and baroreceptor sensitivity in patients with syncope.
      ). Many studies used salt tablets (
      • Claydon V.E.
      • Hainsworth R.
      Salt supplementation improves orthostatic cerebral and peripheral vascular control in patients with syncope.
      ;
      • Zhang Q.
      • Liao Y.
      • Tang C.
      • Du J.
      • Jin H.
      Twenty-four-hour urinary sodium excretion and postural orthostatic tachycardia syndrome.
      ;
      • El-Sayed H.
      • Hainsworth R.
      Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope.
      ;
      • Shichiri M.
      • Tanaka H.
      • Takaya R.
      • Tamai H.
      Efficacy of high sodium intake in a boy with instantaneous orthostatic hypotension.