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PRIORITY PRESS - The Canadian Society of Hospital Pharmacists Annual Professional Practice Conference

Toronto, Ontario / February 4-8, 2012

Toronto - Hyponatremia is among the most common electrolyte disturbances encountered in hospitalized patients. Until recently, the heterogeneous treatment approaches have often been ineffective or potentially risky. There are many causes of hyponatremia, but it most often presents as true hypovolemia due to gastrointestinal losses; euvolemia due to either neurotrauma, neurosurgery or malignancy; edematous hyponatremia due to heart failure; or cirrhosis. Many aspects of current management strategies depend on its presentation but vaptan agents, which inhibit the action of vasopressin, are expanding the options for all causes of non-hypovolemic hyponatremia. Studies in decompensated heart failure indicate that these treatments are safe in this setting and that patients who are hyponatremic at the time of treatment benefit relative to placebo. 

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec 

According to key opinion leader Dr. Sheldon Tobe, University of Toronto, Ontario, management of hyponatremia is too heterogeneous, and physicians need to standardize their approach to this common electrolyte abnormality to ensure patients receive the most effective and least risky strategy possible.

“Hyponatremia is the most common electrolyte disturbance we see,” Dr. Tobe told delegates here at the CSHP. It is defined as an excess of water in relation to sodium (Na+) in extracellular fluid resulting in Na+ <135 mmol/L. Among its 5 main presentations, true hypovolemia is most likely caused by gastrointestional (GI) losses (vomiting/diarrhea). Patients who are euvolemic typically have the so-called syndrome of inappropriate anti-diuretic hormone (SIADH) which is usually caused by neurotrauma, neurosurgery or malignancy.

“Edematous patients are actually volume-overloaded,” Dr. Tobe added; most commonly, edematous hyponatremia is caused by heart failure (HF) and cirrhosis. In addition to multiple medical conditions that can cause low serum Na+, diuretics and NSAIDs are also responsible.

Associated Risks

If low serum Na+ was a benign electrolyte abnormality, the appropriate management approach would not be so critical. But studies show that regardless of its etiology, hyponatremia increases hospital length of stay (LOS) as well as mortality. For example, LOS among patients who presented with NA+ <126 mmol/L in one study (Nephrol Dial Transplant 2006;21:70-6) was 18.2 days while it was 30.7 days for patients who developed new Na+ <126 mmol/L once hospitalized.

In another study (Arch Intern Med 2010;170:294-302), patients who were admitted to hospital with NA+ <127 mmol/L had a greater than 17-fold risk of mortality compared to those who were admitted with normal NA+ levels (138-142 mmol/L). Mortality risk was still more than fourfold greater among those who had less severe hyponatremia (128-132 mmol/L) in the same study compared to those with normal nadir levels. “These patients are really sick,” Dr. Tobe remarked, “and when we add a completely heterogeneous way of managing them, you are not doing them any favours.”

In the truly hypovolemic patient, too rapid a correction or overcorrection of a low serum Na+ can result in osmotic demyelination. As Dr. Tobe offered as an example, if sodium concentration drops acutely from 140 mmol/L to 120 mmol/L, “the brain is surrounded by this hypotonic fluid and since the brain is an intracellular organ, free water is going to rush into the brain and it is going to swell and intracranial pressures will rise.” If, on the other hand, patients are made hypernatremic, “we raise their serum Na+ and they will get a shrunken brain.” One of the key rules when correcting low serum Na+ is not to allow the Na+ to correct more than 0.5 mmol/L every hour.

Older Strategies, New Approaches

The major advance has been the introduction of vasopressin V₂ receptor antagonists or vaptans. These circumvent many of the limitations of the previous options for correcting low serum Na+. For example, the isotonic salines are ineffective in dilutional hyponatremias and cannot be used in edema-forming disorders. Overcorrection of Na+ with hypertonic salines can cause osmotic demyelination and there is no consensus on appropriate infusion rates. Fluid restriction is also ineffective when vasopressin levels are high and is poorly tolerated due to thirst. Urea is actually not approved for hyponatremia; moreover, patients dislike its taste, as Dr. Tobe noted.

True hypovolemic patients should still be treated traditionally with free water restriction and the use of normal saline to replace volume. After restoration of euvolemia, the urine should be “locked” with desmopressin, a synthetic replacement for vasopressin to prevent too rapid correction of sodium levels.

As discussed by Dr. Peter Liu, University of Toronto, approximately 20% of patients with acute HF are hyponatremic to some degree; as is the case with other comorbidities, the presence of hyponatremia increases mortality risk in patients with HF as well. In the OPTIMIZE-HF registry, for example (Eur Heart J 2007;28:980-8), admission serum Na+ levels lower than 135 mmol/L were associated with a higher in-hospital mortality rate. Admission serum Na+ remained a significant independent predictor of in-hospital mortality, post-discharge mortality and 60- and 90-day death or rehospitalization rates in multivariate analysis. “In the setting of HF, there is a tremendous increase in underlying neurohormonal drive,” Dr. Liu told delegates.

Levels of vasopressin, an anti-diuretic hormone, are inappropriately activated in the presence of HF as well and stimulation of the vasopressin V₂ receptors in the kidneys results in increased reabsorption of water and volume expansion. “Indeed, the level of vasopressin very much tracks the degree of HF so the worse the HF, the higher the vasopressin levels,” Dr. Liu explained.

V₂ receptor antagonists reverse these effects. So far, oral tolvaptan is the only V₂ receptor antagonist approved for the treatment of non-hypovolemic hyponatremia in Canada. By antagonizing the V₂ receptor on renal cells, tolvaptan decreases water reabsorption and results in a net increase in free water excretion. Unlike the diuretics which promote excretion of both free water and Na+, vasopressin antagonists only promote the excretion of free water, consequently increasing serum Na+ concentrations, as Dr. Liu noted.

Corroborative Evidence

The benefit of this mechanism in decompensated HF is supported by findings from the EVEREST Outcomes trial (JAMA 2007;297(12):1319-31), Dr. Liu remarked. This study was designed to investigate the effects of tolvaptan in patients hospitalized with acute decompensated HF and symptoms of volume overload. Approximately 4000 patients were randomized to receive either tolvaptan 30 mg/day or placebo plus standard therapy. The study agent was continued for a minimum of 60 days and the median duration of follow-up was 9.9 months.

Overall, 11.5% of the cohort had hyponatremia (Na+<135 mmol/L), 2.2% of whom had severe hyponatremia (Na+ <130 mmol/L). In the overall cohort, there was no difference in either all-cause mortality or cardiovascular (CV) mortality or in hospitalizations for HF. Dr. Liu suggested that “this agent is absolutely safe in the setting of decompensated HF.” However, in the subgroup with Na+ <130 mmol/L, there was a significant decrease in adjudicated CV morbidity and mortality in the active treatment group compared with placebo (P<0.05). The vasopressin antagonist also produced consistent and lasting increases in serum Na+ in patients with hyponatremia, with rises in serum Na+ occurring within the first day of treatment. Self-assessed dyspnea also improved significantly for the overall cohort in favour of the study agent (P<0.0001). There was a greater reduction in body weight from day 1 to day 7 of about 1.6 lbs. (0.726 kg) in favour of the vasopressin antagonist group as well.

Indications

As Dr. Liu confirmed, tolvaptan is currently indicated for the treatment of clinically important, non-hypovolemic hyponatremia (serum Na+ <130 mmol/L) as well as symptomatic hyponatremia. The starting dose is 15 mg q.d. with titration at intervals of 24 hours or more up to a maximum of 60 mg/day. It has not been studied in patients with serious neurological symptoms requiring urgent correction of serum Na+. Consequently, neurological patients requiring urgent intervention to raise serum Na+ should not be treated with this agent.

Treatment should only be initiated in hospitals where serum Na+ can be monitored closely by physicians experienced in the management of clinically important hyponatremia, as Dr. Liu reminded delegates.

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