Complications and Management of Hyponatremia

Richard H. Sterns; Stephen M. Silver


Curr Opin Nephrol Hypertens. 2016;25(2):114-119. 

In This Article

Managing Mild Hyponatremia

Because of the many adverse effects associated with hyponatremia, maintenance of a normal serum sodium is a desirable goal in all patients. The availability of vasopressin antagonists, tolvaptan, and conivaptan, now makes it possible to achieve normonatremia in most patients with euvolemic or hypervolemic hyponatremia.[47] Their mechanism of action explains why vasopressin antagonists should be reserved for mild hyponatremia in ambulatory patients, or minimally symptomatic hyponatremia in hospitalized patients, and should not be used in hyponatremic emergencies. Vasopressin binds at a superficial site on the vasopressin receptor, located on the blood side of the collecting duct cell membrane, whereas vasopressin antagonists penetrate deeply into the membrane, altering the ability of vasopressin to bind to its receptor in the adjacent loop. The antagonists prevent insertion of water channels into the apical membrane, inhibiting reabsorption of water and generation of concentrated urine, but a maximum aquaresis is delayed by 2 h. In clinical trials, tolvaptan caused only a small increase in serum sodium within 8 h, and 12 h after conivaptan only half the patients had corrected by more than 4 mEq/l. Approximately 15% of patients fail to respond, possibly because of high plasma vasopressin levels that cannot be overcome by the competitive antagonist, or because of vasopressin-independent impairments in water excretion. Because vasopressin antagonists can result in overcorrection of hyponatremia,[48] the serum sodium concentration should be monitored at 4-h intervals after their administration, and once an increase of 6–8 mEq/l has been achieved, urinary water losses should be replaced oral water or i.v. 5% dextrose in water.[47]

The chief barriers to the use of vasopressin antagonists in ambulatory patients is their high cost, the absence of outcome data showing that an improved serum sodium concentration improves outcomes, and concerns about hepatic toxicity.[32,47] A registry of 3087 patients with a serum sodium of less than 130 mEq/l from 225 sites in the USA and Europe found that only 4% were treated with tolvaptan.[49] After abnormal liver function tests were identified in a clinical trial using high doses of tolvaptan for polycystic kidney disease, the US Food and Drug Administration issued a recommendation limiting the use of tolvaptan to 30 days and advising against its use in patients with liver disease. We endorse the conclusion of a recent review that patients awaiting liver transplantation should be considered an exception to this advice, because hyponatremia increases the risk of osmotic demyelination after transplantation.[47]

Citing concerns about outcomes, cost, and toxicity, the European Clinical Practice Guideline recommends against the use of vasopressin antagonists for any indication.[32] The European Guideline recommended treatment with oral urea, an agent that increases urinary water excretion by causing an osmotic diuresis.[32] Although urea has been shown to be effective in both inpatient and ambulatory settings, it has not been subjected to placebo controlled trials, and it is not available in pharmacies.[9,50,51]

There is a pressing need for prospective, controlled trials to identify affordable treatments for mild hyponatremia that reduce the need for hospitalization, decrease hospital length of stay, and decrease morbidity. Such trials could also help answer the question of whether hyponatremia causes excess mortality or whether it is simply a marker for severe, lethal, underlying disease.[47]