Thursday, July 09, 2009

Hyponatremia and seizures

Hyponatremia may be the most common electrolyte disturbance seen in hospitalized patients. It is the most likely to lead to permanent or lethal complications if treated incorrectly. Recently, a new class of therapeutic agents called “aquaretics” have become available and will simplify the treatment of hyponatremia. To realize the promise of these new agents, it is important to understand how hyponatremia develops, how the body responds to the disturbance, and how to make therapeutic interventions that improve symptoms caused by hyponatremia without causing iatrogenic injury (Am J Med 2007;S1-21).


Hyponatremia is caused by water retention (N Engl J Med. 2000;342:1581-1589). Except for patients with renal failure whose inability to eliminate excess water is independent of hormonal controls, failure to inhibit secretion of the antidiuretic hormone, vasopressin, in response to hypo-osmolality is responsible for almost all cases of hyponatremia in the hospital (Table 1). In hyponatremia caused by hypovolemia, heart failure, or hepatic cirrhosis, nonosmotic release of vasopressin is a response to an inadequate circulation and patients retain both water and salt. In hyponatremia caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH), nonosmotic release of vasopressin occurs without a hemodynamic stimulus and patients retain water while excreting all the salt that is given to them( N Engl J Med. 2007:356:2064-2072).

Two receptor subtypes (V1A and V2) mediate vasopressin's major physiologic effects. V1A receptors are located on vascular smooth muscle cells and cardiac myocytes, affecting vascular tone and myocardial function (Circulation. 2008;118:410-421). V2 receptors are located on cells lining the kidney's collecting duct; activation of the V2 receptor inserts vasopressin-sensitive water channels in the cell membrane, promoting the reabsorption of water and elaboration of a concentrated urine. Physiologic inhibition of vasopressin secretion or pharmacologic blockade of vasopressin V2 receptors causes an “aquaresis,” the excretion of increased volumes of dilute urine without an increase in sodium or potassium excretion (Lancet. 2008;371:1624-1632). The elimination of electrolyte-free water in the urine returns the serum sodium to normal.

Consequences of hyponatremia

Because the blood-brain barrier is much more permeable to water than to salt, a low serum sodium concentration creates an osmotic force that drives water into the brain( Am J Med. 2006;119[7 Suppl 1]: S12-16). Hyponatremia that develops over a few hours (e.g., in patients given hypotonic fluids after surgery or in patients with self-induced water intoxication associated with psychosis, competitive running, or use of the amphetamine ecstasy) causes life-threatening cerebral edema and symptoms of headache, nausea, vomiting, confusion, and obtundation. There often follows an explosive onset of seizures, coma, respiratory arrest and, rarely, death from herniation of the brain.

Given a day or two, the brain adapts to osmotic swelling by shedding cellular solutes so that the osmolality of brain cells and the plasma can be equal without an increase in cell water content. The adaptive loss of organic osmolytes from brain cells minimizes brain swelling in chronic hyponatremia and permits survival despite extremely low serum sodium concentrations. However, the loss of solute from the brain causes reversible neurologic symptoms and makes the brain vulnerable to injury if the serum sodium concentration is normalized too rapidly. Too great a correction of hyponatremia in too short a time shrinks brain cells and initiates a progressive and often permanent neurologic syndrome known as “osmotic demyelination or central pontine and extrapontine myelinolysis”( N Engl J Med. 1986;342:1535-1542).

Hyponatremia is associated with increased hospital mortality, likely reflecting the severity of illnesses that cause hyponatremia (severe heart failure, end-stage liver disease, respiratory failure, malignancies, renal failure, etc.). Fatal cases are rarely associated with evidence of cerebral edema or osmotic demyelination; in other words, patients die with hyponatremia and not from hyponatremia. However, it remains possible that non-neurologic effects of hyponatremia not yet understood are responsible for the poor outcomes that have been recorded.

Acute hyponatremia

Symptomatic acute hyponatremia is a true emergency that demands prompt and definitive intervention. Because minor degrees of cerebral edema can be catastrophic in patients with elevated intracranial pressure caused by underlying neurologic or neurosurgical disease, patients with intracranial hemorrhage, brain tumors, or central nervous system infections who become symptomatically hyponatremic should also be treated urgently. In 2008, an expert panel released guidelines on treating acute hyponatremia in runners (Clin J Sport Med, 18:111-21, 2008 ); the panel's recommended regimen can be applied to all hyponatremic emergencies. ()

An increase in serum sodium concentration of 4-6 mmol/L is enough to stop seizures caused by hyponatremia and to prevent herniation. If life-threatening cerebral edema is suspected, a bolus infusion of 100 mL of 3% saline should be given to acutely reduce brain edema, with up to two additional bolus infusions of 3% saline given at 10-minute intervals if there is no clinical improvement. This regimen translates to a maximum of 6 mL/kg of 3% saline in a 50-kg woman, enough to increase the serum sodium concentration by 5-6 mmol/L. Once the bolus therapy has been completed, further treatment with hypertonic saline may be unnecessary. Because not all patients respond to aquaretics, these agents cannot be recommended as monotherapy for hyponatremic emergencies.

Chronic hyponatremia

Treatment is indicated for all hospitalized patients with hyponatremia. Even hyponatremia that appears to be “asymptomatic” is associated with an increased risk of falls and fractures and can be shown on formal testing to cause gait disturbances and disturbed cognition. Severe chronic hyponatremia usually causes moderate but distressing symptoms (e.g., weakness, confusion, delirium, gait disturbances, muscle cramps, nausea, and vomiting) that improve with treatment. Seizures are uncommon, but they can occur in patients who present with extremely low serum sodium concentrations or who have pre-existing seizure disorders or alcohol withdrawal.

Overcorrection of chronic hyponatremia risks iatrogenic brain damage. Although no therapeutic limit is absolutely safe, observational studies suggest that correction of serum sodium concentrationby more than 10 mmol/L in 24 hours or 18 mmol/L in 48 hours is unnecessary and risky. These are limits that should not be exceeded and not therapeutic goals to be reached. Therapy should be designed to keep patients safe from serious complications of hyponatremia while staying well clear of correction rates that risk iatrogenic injury. Thus, the following targets are appropriate in most cases: increase in serum sodium concentration of 6 to 8 mmol/L in 24 hours; 12 to 14 mmol/L in 48 hours; and 14 to 16 mmol/L in 72 hours. For patients with advanced liver disease or severe malnutrition who are at very high risk for osmotic demyelination, even slower daily rates of correction are indicated.

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.

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.


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