Therapeutic options

Fluid restriction. Unless the patient is excreting a maximally dilute urine, fluid restriction (typically less than one liter daily) is a needed adjunct to therapy.However, if the cause for water retention persists, fluid restriction alone will increase the serum sodium concentration by little more than 1-2 mmol/L per 24 hours.The urinary cation concentration (sodium plus potassium) divided by the plasma sodium concentration can help predict the response to fluid restriction. If the ratio is less than 0.5 (meaning that electrolyte-free water clearance is positive), correction of hyponatremia is likely to be prompt (and often faster than intended), and fluid restriction need not be stringent. If the ratio is equal to 1.0 or higher (meaning no electrolyte-free water clearance), hyponatremia is likely to be recalcitrant to water restriction alone.

Potassium. If the patient is hypokalemic, administration of potassium will help increase the serum sodium concentration. Hourly IV “runs” of potassium chloride 10 mmol in 100 mL of normal saline, which has a cation concentration of 254 mmol/L (almost always higher than the urine cation concentration), will reliably correct hyponatremia and hypokalemia in potassium-depleted patients.

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Isotonic saline. Elimination of a volume stimulus for vasopressin secretion results in an aquaresis. However, if vasopressin is secreted for a reason other than volume depletion (e.g., SIADH caused by nausea, pain, surgical stress, respiratory infections, tumors, neurologic conditions, or medications), isotonic saline is ineffective. If the urine cation concentration exceeds 154 mmol/L, infusion of isotonic saline may actually lower the serum sodium concentration (Ann Intern Med. 1997;126:20-25).  Isotonic saline will not improve hyponatremia caused by hepatic cirrhosis or heart failure, and it will worsen edema. Therefore, isotonic saline should be reserved for hyponatremic patients who require volume resuscitation for hypotension or patients with mild hyponatremia who will not be harmed if the serum sodium concentration fails to improve with this therapy.

Hypertonic saline. Many hospitalized patients present with multiple potential causes for hyponatremia. Therefore, it is often prudent to begin therapy with hypertonic saline or a vasopressin antagonist. Hypertonic saline will reliably increase the serum sodium concentration regardless of etiology. A slow infusion of 3% saline at 15-30 mL/hr can be used for chronically hyponatremic patients with mild-to-moderate symptoms (Clin J Am Soc Nephrol. 2007;2:1110-1117). Chemistries should be obtained at 4- to 6-hour intervals during the infusion, and the urine output should be carefully monitored. Hypertonic saline should be discontinued after the serum sodium has increased by 4-6 mmol/L or if an aquaresisemerges.   

Loop diuretics. Loop diuretics interfere with the kidney’s concentrating ability and therefore are indicated in patients with hyponatremia caused by heart failure. Thiazide diuretics, on the other hand, are contraindicated in hyponatremic patients. Loop diuretics can be combined with hypertonic saline or oral salt tablets (9 g of sodium chloride daily is equivalent to 300 mL of 3% saline); potassium replacement or administration of a potassium-sparing diuretic, such as amiloride, may be necessary to avoid hypokalemia from this maneuver. 

Aquaretics. Conivaptan, which blocks both V2 and V1A receptors, is currently the only vasopressin antagonist available for use in the United States. At least two orally active selective V2-receptor antagonists are currently seeking approval from the FDA. Because conivaptan interacts with many medications, the drug is approved only for the short-term management of hyponatremia in hospitalized patients. Conivaptan is contraindicated in volume depletion because antagonism of the V1A receptor could cause hypotension.

Moreover, this agent cannot be recommended in patients with cirrhosis and ascites because hepatorenal syndrome is improved by agonists of the V1A  receptor and administration of a V1A  antagonist could cause this complication. Conversely, antagonism of the hemodynamic effects of the V1A receptor  may be desirable in patients with heart disease; therefore, the drug is approved for the treatment of hyponatremia associated with heart failure as well as for the treatment of euvolemic hyponatremia caused by SIADH.Vasopressin antagonists are likely to be effective in most patients with hospital- acquired hyponatremia. These agents are an especially attractive alternative for patients with heart disease who require treatment of hyponatremia but are intolerant of a salt load (the drug is not indicated for the treatment of congestive heart failure).

Inadvertent overcorrection

Many causes of hyponatremia in hospitalized patients are reversible (e.g., hypovolemia; beer potomania; drug-induced hyponatremia; cortisol deficiency; or self-limited causes of SIADH, such as pain, nausea, hypoxia, alcohol withdrawal, or recent surgery). Once the reason for vasopressin secretion resolves, excretion of dilute urine increases the serum sodium concentration very rapidly (by 2 mmol/L or more per hour) and much more than would be predicted by calculations that ignore urine output.

To avoid injury from inadvertent overcorrection of hyponatremia, urine output should be carefully monitored in all cases of severe hyponatremia. If an aquaresis emerges, urinary water losses must be replaced or, alternatively, the aquaresis can be terminated by administering the synthetic vasopressin anaolog, desmopressin (Clin J Am Soc Nephrol. 2008;3:331-336, 2008).

Desmopressin has been used clinically as a therapeutic agent to avoid overcorrection of hyponatremia and to return the plasma sodium concentration to lower levels after inadvertent overcorrection.The drug can be given as soon as the targeted initial increase in serum sodium concentration (approximately 6-8 mmol/L) has been achieved or as soon as an aquaresis is recognized.

A dosing interval of 6 or 8 hours, rather than the twice-daily dosing schedule used in patients with diabetes insipidus, is recommended initially. Less frequent dosing can be used later to allow water losses to further increase the serum sodium. Alternatively, desmopressin can be continued, maintaining an antidiuresis until the serum sodium has been increased to the mildly hyponatremic range with the concurrent administration of hypertonic saline.

Administration of high-dose desmopressin to terminate an aquaresis induced by vasopressin antagonists is a theoretically attractive, but as yet, untested strategy that would allow more therapeutic precision than is currently possible. While awaiting more data, clinicians using vasopressin antagonists to treat hyponatremia are advised to closely monitor urine output and be prepared to match urinary water losses to avoid inadvertent overcorrection.

Dr. Sterns is Professor of Medicine at the University of Rochester School of Medicine and Dentistry and Chief of Medicine at Rochester General Hospital, both in Rochester, N.Y. More in-depth information on this important topic is provided in a paper recently coauthored by Dr. Sterns and two colleagues and scheduled to appear later this year in Seminars in Nephrology.