Hyponatremia due to SIADH requiring Tolvaptan

Today Nicole presented an interesting case with multiple turns which started out with pre-septal cellulitis and evolved into a-fib with RVR complicated by likely pulmonary edema as well as clinical concern foTolvaptanr a septic arthritis of the knee joint with current cultures pending. Amidst his hospital course the patient developed what appeared to be euvolemic hyponatremia with urine/serum osm studies suggest of SIADH. His SIADH was relatively treatment refractory, not responding well to fluid restriction, urea, or hypertonic saline while in the MICU. Ultimately, it did improve with escalating doses of tolvaptan.

Tolvaptan is a vasopressin receptor (ADH) antagonist that selectively targets the V2 receptor which mediates the antidiuretic response. It helps produce a selective water diuresis without affecting sodium or potassium excretion. The original SALT trials supporting its use was published in NEJM in 2006 and this study took hyponatremic patients with either euvolemic or hypervolemic hyponatremia and compared tolvaptan (initial dose 15 mg daily, escalated to 30 mg and then 60 mg based on Na concentrations) versus placebo. It found that the serum sodium concentration was statistically significantly higher at both 4 days and 30 days compared to placebo. However, after discontinuation after 30 days of treatment the hyponatremia recurred back to similar prior values. Major side effects included increased thirst, dry mouth, and increased urination. The patients do benefit by having to adhere to less fluid restriction.
 The attached study is a subsequent analysis of patients enrolled in these SALT trials whose indication was for SIADH. Similarly, patients had a statistically significant increase in sodium at day 4 and day 30, similar side effects. 5.9% of the patients had overly rapid correction of their hyponatremia. Regarding surveys based on symptoms, there was a statistically significant treatment effect favoring tolvaptan for the physical component, and a near-significant trend favoring tolvaptan for the mental status component of the SF-12 Health Survey.
There are limitations to the use of tolvaptan, mainly concerns about a greater than 2.5 fold increase in liver enzymes. For this reason, it should not be used > 30 days and should not be used in patients with liver disease. Other considerations include concerns about rapid overcorrection of sodium. Given the limitation to 30 days, it is best used in severe hyponatremia and when cause of SIADH may be reversible. Tolvaptan can also be cost prohibitive.