Blood Pressure Regulation in Autonomic Failure By Dietary Sodium, Blood Volume and Posture

Abstract

In normal subjects natriuresis is tightly coupled to dietary salt ingestion to maintain sodium balance. Likewise, blood pressure remains unchanged over a wide range of salt intake because of pressure natriuresis, whereby an increase in blood pressure stimulates renal sodium excretion to restore homeostasis. These sodium handling mechanisms are impaired in autonomic failure. When exposed to salt restriction, autonomic failure patients are unable to reduce renal sodium excretion, and their orthostatic hypotension worsens. It follows that increased dietary salt would improve orthostatic tolerance. Indeed, most clinical practice guidelines emphasize a high salt intake (6–10 gm/day) in the treatment of neurogenic orthostatic hypotension. This approach has been shown to improve other conditions such as syncope and postural tachycardia syndrome, but surprisingly there is no empirical evidence to support this recommendation in orthostatic hypotension. Even though there is expert opinion consensus in its favor, it would be reassuring if at least mechanistic proof of concept studies were available. Fludrocortisone is often added to a high salt diet to improve sodium retention and increase plasma volume, but these effects are transient. Fludrocortisone is contraindicated in patients with heart failure and should be use with caution, if at all, if supine hypertension is present. In patients with supine hypertension posture is an important determinant of sodium balance; blood pressure substantially increases while supine, triggering pressure natriuresis and extensive sodium loss. Thus, avoiding the supine posture may be as important as increasing dietary salt in the management of orthostatic hypotension.

1. Introduction

Sodium balance is tightly controlled in normal subjects, whereby an increase in dietary sodium is accompanied by an increase in urinary sodium excretion, and a perfect balance between sodium intake and excretion is achieved in a few days. Blood pressure also remains constant between a wide range of dietary sodium because of the pressure-natriuresis curve, whereby an increase in blood pressure induces renal natriuresis, ultimately restoring blood pressure. These mechanisms, aimed at maintaining blood volume and blood pressure homeostasis, are impaired in patients with neurogenic orthostatic hypotension due to autonomic failure, as we will review herein.

The most severe cases of neurogenic orthostatic hypotension are associated with primary neurodegenerative diseases of the autonomic nervous system due to alpha-synuclein deposits forming neuronal Lewy bodies in peripheral autonomic fibers (Parkinson’s disease, pure autonomic failure, dementia with Lewy bodies), or glial cytoplasmatic inclusions in the CNS (multiple system atrophy). These patients present a unique opportunity to examine the role of the autonomic nervous system on the regulation of blood pressure by dietary sodium and blood volume (Biaggioni, 2007). In these patients, autonomic impairment is associated with abnormalities in the renal handling of dietary sodium, and in the relationship between plasma volume and blood pressure. Autonomic neuropathies secondary to systemic diseases, such as diabetes mellitus or amyloidosis are often associated with impairment of renal function and heart failure, and will not be discussed here.

2. Sodium Handling and Salt Supplementation in Autonomic Failure

In normal subjects there is dense sympathetic innervation to the kidneys, mostly on smooth muscle cells residing in the renal vasculature but also on epithelial cells residing in the renal tubules. Norepinephrine released from renal sympathetic nerves acts directly on renal epithelial cells to increase sodium and water reabsorption from the proximal tubule and thick ascending limb of Henle’s loop. Changes in renal blood flow and glomerular filtration rate also contribute to sympathetically-induced decreases in renal excretion of salt and water.

These mechanisms of salt conservation are lost in autonomic failure, and in contrast to normal subjects, autonomic failure patients are unable to reduce sodium excretion in a setting of dietary sodium restriction. After one week of sodium restriction autonomic failure patients loose 3 times as much body weight as normal subjects. The decrease in plasma volume is comparable to that of normal subjects, suggesting that the exaggerated weight loss is due to interstitial fluid loss. Nonetheless, sodium restriction is associated with worsening of orthostatic hypotension (Wilcox et al., 1977).

Patients with autonomic failure have a normal plasma volume on a regular sodium diet (Wilcox et al., 1984). Plasma volume can even be slightly higher in those who have a reduced red cell mass, so that total volume remains normal (Biaggioni et al., 1994). In contrast to normal subjects in whom blood pressure is maintained within a narrow range despite wide changes in plasma volume, blood pressure in patients with autonomic failure is linearly correlated to changes in plasma volume (Wilcox et al., 1984).

Thus, sodium restriction leads to worsening of orthostatic hypotension in autonomic failure patients, but the interaction between plasma volume and blood pressure is complex and not completely understood. Nonetheless, it follows that increase dietary sodium will results in an improvement in orthostatic hypotension. Indeed, increased salt intake is universally recommended for the management of orthostatic hypotension by various societies and expert panels (Brignole et al., 2018; Lahrmann et al., 2006; Shen et al., 2017; Shibao et al., 2013). Recommended daily amounts of sodium chloride vary from 6–10 g. Some recommend guiding salt supplementation based on individual patient’s dietary salt intake reflected in their urinary sodium excretion. Increasing salt in the diet is the preferred approach to increase sodium intake, but if this cannot be achieved, sodium chloride tablets (1 g with meals) are often recommended. Salt tablets, however, may not be tolerated by some patients because of GI upset.

Despite the strong recommendation for salt supplementation, there is little evidence from clinical trials to support these guidelines. The only systematic review of the evidence for salt supplementation refers to “orthostatic intolerance” syndromes (Loughlin et al., 2020) and not specifically to neurogenic orthostatic hypotension due to autonomic failure. Supportive evidence cited in the guidelines come from small number of clinical trials including a limited number of patients for relatively short periods, but none of these studies have been conducted in patients with autonomic failure. The most frequently cited carefully conducted study indeed showed that salt supplementation improves plasma volume and orthostatic tolerance, but it was done in patients with unexplained syncope without a neurological disease (El-Sayed et al., 1996). The only other study we are aware that addresses this subject, included young patients (average age of 35 years) with mild forms of orthostatic hypotension (average drop in systolic blood pressure on standing of 25 mm Hg) of unclear etiology (Pechere-Bertschi et al., 1998). Similarly, other trials cited as evidence of the beneficial effects of increased dietary salt have been performed in patients referred for syncope, postural tachycardia syndrome or chronic fatigue syndrome (Loughlin et al., 2020).

3. Alternative Approaches to Increase Blood Volume in Autonomic Failure

Fludrocortisone, a synthetic mineralocorticoid commonly used in neurogenic orthostatic hypotension to improve sodium retention and increase plasma volume, is often added to improve the efficacy of salt supplementation. Fludrocortisone is contraindicated in the presence of heart failure, a common comorbidity in patients with neurogenic orthostatic hypotension, and should be use with caution, if at all, in patients with supine hypertension. In general, fludrocortisone is associated with more adverse outcomes compared to midodrine (Grijalva et al., 2017).

Fludrocortisone increases interstitial and intravascular volume, but this effect is transient, and after 1–2 weeks of continuous use plasma volume returns to baseline values (Chobanian et al., 1979). Arguably, it would be preferable to selectively increase intravascular volume, and the most efficient approach of doing this would be to improve anemia, which in autonomic failure patients is related to impaired erythropoietin production and is reversed by treatment with recombinant erythropoietin (Biaggioni et al., 1994; Hoeldtke et al., 1993). The severity of anemia is usually mild (hemoglobin ~ 11 g/dl) and would not justify treatment with recombinant erythropoietin. Nonetheless, this treatment is very effective in improving orthostatic hypotension, but it often requires increasing hemoglobin to normal values, an approach that has raised safety concerns because of increased cardiovascular events in patients with end-stage renal disease (Singh et al., 2006). More recent studies have suggested that exposure to high dosages of erythropoietin, rather than raising of the hemoglobin concentration, explains this increased risk (Singh, 2011). In a large observational study, adverse outcomes associated with the use of erythropoietin were greater in diabetic patients and in those using doses higher than 40,000 U/week. By comparison, autonomic failure patients require much lower doses (6,000–12,000 U/week) to normalize hematocrit. Thus, it is not certain if these safety concerns apply to patients with autonomic failure, but clinical trials to determine safety and efficacy are not like forthcoming.

4. Effect of Posture and Pressure Diuresis in Sodium Handling

The effect of dietary salt in autonomic failure is further complicated by the dramatic influence posture has on renal sodium handling in these patients. A majority of patients with neurogenic orthostatic hypotension also suffer from supine hypertension, which can be severe and complicates the management of orthostatic hypotension (Arnold et al., 2012; Fanciulli et al., 2018; Jordan et al., 2002; Jordan et al., 2019; Shannon et al., 1997). The hemodynamic mechanism of the supine hypertension of autonomic failure is an increase in systemic vascular resistance, rather than an increase in cardiac output or blood volume (Kronenberg et al., 1990), and there is no correlation between plasma volume and supine hypertension in autonomic failure patients (Shannon et al., 1997).

As mentioned previously, in normal subjects blood pressure remains constant between a wide range of dietary sodium because of pressure-natriuresis. Not only is this mechanism impaired by renal denervation (Yoshida et al., 1991), but autonomic failure patients are exposed to a range of blood pressures not seen in any other condition, simply by going from the supine to the upright posture. In one of our in autonomic failure patient cohort, supine blood pressure was 185 mmHg and dropped 80 mm Hg on standing (Jordan et al., 1999). The normal diurnal pattern of diuresis was reverse, so that urinary volume was 670 ml during the day, and almost twice as much during the night. Because of pressure natriuresis, patients lost about 70 mmol sodium each night (Jordan et al., 1999). Sleeping in a head-up tilt position can reduce nighttime pressure natriuresis (Ten Harkel et al., 1992), but the degree of tilt required to effectively reduce blood pressure limits the usefulness of this approach. Application of local heat may reduce supine hypertension and pressure natriuresis in some patients (Okamoto et al., 2021) but more research is needed to define predictors of response.

Considering that the recommended dietary sodium intake is at least 6 gm of salt, or about 104 mmol sodium/day, patients can lose most of their recommended daily sodium intake at night just because of pressure natriuresis. Therefore, posture can be as important a determinant of sodium balance as dietary sodium, and the more patients stay supine, the more difficult it will be to meet their recommended sodium balance.

5. Conclusions

In summary, current clinical practice guidelines and expert opinion recommend a daily dietary salt intake of 6–10 g of salt as part of the management of neurogenic orthostatic hypotension. Orthostatic hypotension does worsen if autonomic failure patients are placed on sodium restriction, as these patients are unable to reduce natriuresis in this setting; however, we are not aware of evidence from clinical trials supporting the notion that increase dietary salt improves orthostatic hypotension. Clinical trials testing the efficacy of salt supplementation are unlikely to be forthcoming, and in their absence, we do support this recommendation based on the understanding of the underlying pathophysiology. It would be reassuring to have proof of concept mechanistic trials supporting this concept. Fludrocortisone can be used as a way to improve sodium retention, but these effects are transient. The drug is contraindicated in patients with heart failure, and should be use with caution, if at all, in patients with supine hypertension. The use of recombinant erythropoietin is arguably the most effective approach to improve intravascular volume, but its use is controversial because of safety concerns. There is a complex relationship between sodium intake, plasma volume and blood pressure in autonomic failure patients. Because of pressure diuresis, posture may be as important in determining sodium balance as dietary intake and avoiding the supine posture may be as important as increasing dietary salt in autonomic failure patients.