Use of Tolvaptan to Treat SIADH-induced Hyponatremia in Selected Patients With Acute Neurological Injuries

Hyponatremia occurs frequently in patients with acute brain injury in the days to weeks following the acute injury, and may contribute to adverse outcome (1). In addition, hyponatremia can aggravate neurologic dysfunction, complicate neurological assessments, and contribute to neurologic symptoms such as gait dysfunction that can impair efforts at mobilization and rehabilitation. Strict normonatremia (serum Na levels between 135 and 145 meq/dl) is the goal in most patients with acute brain injury.

Various studies have shown that SIADH (syndrome of inappropriate anti-diuretic hormone secretion) is by far the most frequent cause of hyponatremia in patients with acute neurological injuries (1-4). However, the most frequently recommended standard therapies for SIADH such as fluid restriction are often impractical, counter-indicated or impossible to implement in neurocritical patients. For example, patients admitted for subarachnoid hemorrhage (SAH) require maintenance of a euvolemic state to prevent vasospasms; often, high volumes of fluid are required to prevent even brief episodes of hypovolemia, as these may trigger vasospasms [5-8].

Thus many patients are treated with hypertonic saline, which is usually effective, but at the price of inducing hypervolemia with possible (worsening of) cardiac dysfunction (which also occurs very often in patients with acute brain injury, again in particular those with SAH). In addition, using hypertonic saline may require central venous access and ICU monitoring, preventing transfer to a step-down unit in otherwise stable patients.

The investigators plan to use Tolvaptan (Samsca), an oral ADH antagonist that promotes aquauresis, as an agent to treat neurologically and hemodynamically stable patients with acute neurological injuries and suspected SIADH. As this drug is currently approved for 1-month use in patients with SIADH, and patients with acute brain injury develop transient SIADH with a duration of days to weeks, Tolvaptan would in theory be tailor-made for this population. However, experience with Tolvaptan in neurocritical patients is very limited. Current local hospital protocols call for maintaining normonatremia in all patients with acute brain injury (except for patients with brain edema being treated with hypertonic saline to induce hypernatremia). Hyponatremia is usually treated with hypertonic saline at this time.

The investigators aim to use Tolvaptan in patients admitted to the neurological ICU who have developed SIADH, who have recurrence of hyponatremia after discontinuation of hypertonic saline that was initially given to correct hyponatremia, and in neurologically stable patients who develop hyponatremia in the days (up to one week) after admission. Tolvaptan will be given for a 3 day period, then DC-ed but restarted immediately if sodium levels drop below 135 meq. The maximum treatment duration is 14 days.