Management of hyponatremia: Providing treatment and avoiding harm

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How to prescribe fluid restriction rationally

Ideally, patients should not ingest any more fluid than they can excrete in urine and insensible losses—otherwise, the serum sodium can continue to decrease.

Water excretion can be estimated from solute intake and urine osmolarity. In theory, a 70-kg person with a typical daily solute intake of about 10 mOsm/kg and intact urinary dilution to a urine osmolarity of 50 mOsm/L can excrete up to 14 L of urine (700 mOsm/50 mOsm/L) per day. However, a patient with the syndrome of inappropriate ADH secretion (SIADH) and a fixed urine osmolality of 700 mOsm/kg would excrete a similar solute load in only 1 L of urine. Thus, any fluid intake in excess of this volume could worsen hyponatremia.

To excrete free water, urinary sodium plus urinary potassium must be less than the serum sodium concentration. In this regard, the necessary degree of fluid restriction can also be estimated made on the basis of the patient’s urinary electrolytes.22

Increased solute intake to augment water excretion

In patients without hypervolemia, solute intake can be increased to augment water excretion. 22 This can be achieved with salt tablets or oral urea. Although urea can be effective, it is not commonly used because it is not available the United States and it has poor gastrointestinal tolerability. In patients whose nutritional intake is limited and who continue to ingest fluids (such as, for example, an elderly patient subsisting on tea and toast) every effort should be made to increase solute intake with high-protein foods or supplements.


Unfortunately, patients often do not adhere to these strategies, as fluid restriction and unpalatable salt tablets or urea can become too burdensome. In such instances, pharmacologic inhibition of vasopressin-mediated water reabsorption can be considered using the following agents.

Demeclocycline (Declomycin) and lithium inhibit the kidney’s response to vasopressin. Because lithium may be nephrotoxic and has unwanted effects on the central nervous system, demeclocycline has become the preferred agent. Given in doses of 300 to 600 mg twice daily, demeclocycline promotes free water excretion, but often takes 1 to 2 weeks of therapy to begin working.

Renal failure due to demeclocycline has been reported in patients with concomitant liver disease.23 Demeclocycline can also cause photosensitivity and is contraindicated in children and pregnant women due to abnormalities in bone and enamel formation. In addition, it can be expensive and may not be covered fully by some prescription plans.

Vasopressin receptor antagonists (‘vaptans’)

ADH, also called vasopressin, interacts with various receptor subtypes, including V1a (causing vasoconstriction, platelet aggregation, inotropic stimulation, myocardial protein synthesis), V1b (causing secretion of adrenocorticotropic hormone), and V2 (causing water reabsorption and release of von Willebrand factor and factor VIII).

Drugs that block V2 receptors in the renal tubule increase water excretion, making them attractive as therapy for some hyponatremic states (Table 6).24,25 These drugs exert their aquaretic effect by causing a decrease in transcription and insertion of aquaporin-2 channels (“water pores”) into the apical collecting duct membrane. As a result, the water permeability of the collecting duct is decreased even in the presence of circulating ADH.

Conivaptan (Vaprisol) is a combined V1a-V2 antagonist that has been approved for the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan inhibits the cytochrome P450 3A4 system and thus may interact with other drugs; therefore, its use has been limited to no more than 4 days of intravenous administration in the hospital setting. The recommended dosage is an initial 20-mg infusion over 30 minutes, followed by continuous infusions of 20 to 40 mg/day. Dosing adjustments in renal and hepatic impairment have not been well defined.

Tolvaptan (Samsca) is an oral selective V2 antagonist that has been studied in patients with euvolemic and hypervolemic hyponatremia. 26 Studies have included patients with congestive heart failure, cirrhosis, and SIADH. Although tolvaptan has not been shown to reduce rates of rehospitalization or death in congestive heart failure, it improves serum sodium, overall fluid balance, and congestive symptoms.27 Tolvaptan has recently been approved for the treatment of euvolemic and hypervolemic hyponatremia.

A recent study has confirmed the longterm efficacy of tolvaptan in 111 patients over a mean duration of treatment greater than 700 days.28 While the clinical benefits of chronic tolvaptan therapy have yet to be clearly demonstrated, this study shows that tolvaptan therapy can result in a sustained improvement in serum sodium concentration without an unacceptable increase in adverse events.29

Lixivaptan (VPA-985), another oral selective V2 receptor antagonist, is being studied in patients with euvolemic and hypervolemic hyponatremia.

Current role of vasopressin antagonists

Current studies of vasopressin antagonists in the treatment of hyponatremia are promising, though definite recommendations are needed to ensure slow, careful correction of hyponatremia. Most studies suggest that these agents provide slow, reliable increases in serum sodium. In one large study of patients with congestive heart failure, serum sodium rose by more than 12 mmol/L in 24 hours in fewer than 2% of patients.26

Notably, no cases of osmotic demyelination syndrome have been reported in these studies. However, it should be noted that therapy was started in the hospital with close monitoring of serum sodium levels and discontinuation of fluid restriction; the incidence of overly rapid correction of sodium may be higher outside of carefully done clinical studies. Clinicians should adopt monitoring strategies similar to those used in these rigorous studies.

At present, there is little experience with vasopressin antagonists in hyponatremic patients with serious signs or symptoms of cerebral edema, and most clinicians still view 3% saline as the gold standard for these patients.

Vasopressin antagonists should not be used in patients with hypovolemic hyponatremia, due to concerns about V1a blockade causing hypotension and about V2 blockade producing water excretion and a worsening of the volume-depleted state.

Recent clinical trials have reported that patients often experience increased thirst while taking these agents. This highlights the need to monitor serum sodium during treatment.

These agents are expensive. Tolvaptan costs about $250 per tablet; conivaptan, which is administered intravenously, may cost a little more per treatment course.

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