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Pathophysiology of Hypervolemic Hyponatremia

Hypervolemic hyponatremia occurs when extracellular sodium is normal or even slightly elevated, but extracellular fluid is greatly elevated. These patients have signs of clinical hypervolemia, such as pitting edema or ascites. Two of the major etiologies of hypervolemic hyponatremia are heart failure (HF) and cirrhosis.1

Pathophysiology of hyponatremia in heart failure2*

Hyponatremia in HF involves a complex interaction of processes. The excessive water and sodium retention characteristic of HF leads to a reduction in glomerular filtration and increased reabsorption into the body. The activation of the renin-angiotensin system (RAS) also enhances water and sodium reabsorption, as well as stimulating the thirst center of the brain, promoting the ingestion of excessive amounts of fluid.

In addition, high levels of the hormone arginine vasopressin (AVP) are found in patients with HF. AVP binds to V2receptors in the collecting ducts of the kidneys, resulting in free water reabsorption rather than excretion in the urine. The AVP activity combines with other dilutional pathophysiologies to result in hyponatremia.

Pathophysiology of hyponatremia in cirrhosis3

Multiple factors lead to the development of hyponatremia in cirrhotic patients. Portal hypertension in cirrhosis leads to decreased systemic vascular resistance, which initiates a cascade of events leading to non-osmotic release of AVP. AVP activity leads to excessive water retention and hyponatremia, accompanied by volume overload. Decreased glomerular filtration rate and cardiac function also contribute to hyponatremia in cirrhosis.

Pathophysiology of hyponatremia in renal disease

Hyponatremia commonly occurs in both acute and chronic renal failure, because the kidneys cannot maximally excrete excess ingested or infused water. Hyponatremia is not very common in nephrotic syndrome unless associated with a substantial decrease in glomerular filtration rate (GFR); however, with severe hypoalbuminemia of <2 g/dL, intravascular hypovolemia may occur and lead to the non-osmotic release of AVP and subsequent retention of fluids, resulting in hyponatremia.1

*VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure and is not approved for this indication. Safety data on use of VAPRISOL in these patients is limited. Consider other treatment options.

REFERENCES: 1. Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120:S1-S21. 2. Greenberg B. Managing hyponatremia in patients with heart failure. J Hosp Med. 2010;5(suppl3):S33-S39. 3. Ross E, Sigal SH. Managing hyponatremia in cirrhosis. J Hosp Med. 2010;5(suppl3):S8-S17.

Indication: VAPRISOL is indicated to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia.
Important Limitations: VAPRISOL has not been shown to be effective for the treatment of the signs and symptoms of heart failure and is not approved for this indication. It has not been established that raising serum sodium with VAPRISOL provides a symptomatic benefit to patients.


VAPRISOL is contraindicated in patients with hypovolemic hyponatremia. The coadministration of VAPRISOL with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir, and indinavir, is contraindicated. In addition, no benefit can be expected in patients unable to make urine.

Hyponatremia associated with heart failure: Safety data on the use of VAPRISOL in these patients are limited. Consider other treatment options.
Overly rapid correction of serum sodium: Monitor serum sodium, volume and neurologic status and if the patient develops an undesirably rapid rate of rise of serum, VAPRISOL should be discontinued. If serum sodium concentration continues to rise, VAPRISOL should not be resumed. Serious neurologic sequelae, including osmotic demyelination syndrome, can result from over rapid correction of serum sodium. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction should be used.
Hypovolemia or Hypotension: For patients who develop hypovolemia or hypotension while receiving VAPRISOL, VAPRISOL should be discontinued, and volume status and vital signs should be monitored.
Infusion site reactions: Serious reactions have occurred. Administer through large veins and change infusion site every 24 hours.

The most common adverse reactions (incidence ≥10%) reported in clinical trials were infusion site reactions (including phlebitis), pyrexia, hypokalemia, headache and orthostatic hypotension.

Potent CYP3A inhibitors may increase the exposure of conivaptan and are contraindicated. Generally avoid CYP3A substrates. Exposure to coadministered digoxin may be increased and digoxin levels should be monitored.

Use in Patients with Hepatic Impairment
In patients with moderate to severe hepatic impairment, initiate VAPRISOL with a loading dose of 10 mg over 30 minutes followed by 10 mg/day as a continuous infusion for 2 to 4 days. If no rise in serum sodium, VAPRISOL may be titrated upward to 20 mg/day.