Tolvaptan for Patients With Acute Neurological Injuries
Tolvaptan for Patients With Acute Neurological Injuries
Hyponatremia occurs frequently in patients with acute brain injury in the days to weeks
 following injury, and may contribute to adverse outcome. 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. SIADH is the most frequent cause of hyponatremia in
 patients with neurological injury; however, treatment with fluid restriction is often
 difficult or contra-indicated, for example in patients with subarachnoid hemorrhage (SAH)
 where intravascular hypovolemia can trigger vasospasms. The aim of this project is to test
 Tolvaptan, an ADH antagonist, as a treatment in selected patients with acute brain injury who
 have developed SIADH.
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.

 A key point of attention will be that the patients receive sufficient fluid intake, either by
 mouth if they are able to eat and drink, via intravenous administration, or a combination of
 both. The minimum fluid intake must be 2500 ml per 24 hours; usually the intake will be
 greater, especially in patients with SAH. Thus fluid intake/fluid administration will be
 closely monitored. In practice, every patient will be on a continuous IV infusion of 80-100
 ml apart from their oral intake.

 Sodium levels will be checked every 4-6 hours, as is already standard practice in patients
 with acute brain injury who develop hyponatremia.

 Primary endpoint: Normalization of sodium levels (level 135-145 meq/dl). Secondary endpoints:
 1. incidence of vasospasms; 2. incidence of pulmonary edema (defined as evidence of edema on
 chest X ray); 3. clinical outcomes, including length of stay in the ICU.

 Safety Liver enzymes will be monitored because a study in patients with autosomal dominant
 polycystic kidney disease, where Tolvaptan was used to slow the progression of the disease,
 reported that prolonged (3 month) administration of high doses (120 mg) of Tolvaptan was
 linked to a (reversible) rise in OT and PT, and in rare cases bilirubin, in some patients
 (9). However, previous studies in patients without polycystic kidney disease using Tolvaptan
 doses up to 60 mg for one year have not reported liver enzyme rises (10-11). The highest dose
 to be used is 45 mg, and the maximum duration will be 2 weeks.

 Tolvaptan is currently used occasionally in daily clinical practice in local neurological
 ICU's. A review of the data on 43 patients (34 SAH, 5 ICH, 2 AIS, 2 post-brain tumor surgery)
 showed that the drug successfully controlled hyponatremia in the patients in whom it was
 used, without side effects being noted (12). Average sodium levels were 129.4 meq before
 treatment and increased to 135.8 meq within 48 hours. Median treatment duration was 5 days
 (average 4.3 days). No significant side effects were noted. Of note, liberal fluid intake was
 ensured in all of these patients.

 Target patient population and number. A total of 80 patients with acute neurological injury;
 a minimum of 30 patients with subarachnoid hemorrhage, 10 patients with intracranial
 hemorrhage, 10 patients with acute ischemic stroke, 10 patients with traumatic brain injury,
 and 10 patients who have undergone elective neurosurgical intervention.

 Inclusion criteria.

 -  Patients with euvolemic or hypervolemic hyponatremia: serum Na <135 meq/dl

 -  Inappropriately high urinary sodium excretion

 Exclusion criteria.

 -  Clinically evident hypovolemic hyponatremia

 -  Recent myocardial infarction or cardiac surgery

 -  Sustained ventricular tachycardia or fibrillation

 -  Systolic blood pressure of less than 90 mm Hg

 -  Serum creatinine concentration of more than 3 mg per deciliter

 -  History of, or biochemical evidence of, liver disease

 -  Serum sodium concentration less than 120 mmol per liter in association with neurologic
 impairment

 -  Urinary tract obstruction

 -  Use of other diuretics (furosemide, burinex, hydrochlorthiazide) that cannot be safely
 discontinued

 -  Concomitant use of hypertonic saline (prior use OK, if hypertonic is stopped within 1
 hour of the first dose of Tolvaptan administration).

 -  History of chronic SIADH or known chronic hyponatremia from other causes (e.g. heart
 failure)

 -  Uncontrolled hypothyroidism or adrenal insufficiency

 -  Severe co-morbidities with life expectancy <6 months

 -  CMO status
Inclusion Criteria:

 -  Patients with euvolemic or hypervolemic hyponatremia: serum Na <135 meq/dl

 -  Inappropriately high urinary sodium excretion

 Exclusion Criteria:

 -  Clinically evident hypovolemic hyponatremia

 -  Recent myocardial infarction or cardiac surgery

 -  Sustained ventricular tachycardia or fibrillation

 -  Systolic blood pressure of less than 90 mm Hg

 -  Serum creatinine concentration of more than 3 mg per deciliter

 -  History of, or biochemical evidence of, liver disease

 -  Serum sodium concentration less than 120 mmol per liter in association with neurologic
 impairment

 -  Urinary tract obstruction

 -  Use of other diuretics (furosemide, burinex, hydrochlorthiazide) that cannot be safely
 discontinued

 -  Concomitant use of hypertonic saline (prior use OK, if hypertonic is stopped within 1
 hour of the first dose of Tolvaptan administration).

 -  History of chronic SIADH or known chronic hyponatremia from other causes (e.g. heart
 failure)

 -  Uncontrolled hypothyroidism or adrenal insufficiency

 -  Severe co-morbidities with life expectancy <6 months

 -  CMO status