A new class of agents called ‘aquaretics’ has joined the list of available therapeutic options
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.
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.
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.