Tolvaptan for Patients With Acute Neurological Injuries
| Status: | Terminated |
|---|---|
| Conditions: | Metabolic |
| Therapuetic Areas: | Pharmacology / Toxicology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/26/2018 |
| Start Date: | August 2015 |
| End Date: | September 2016 |
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 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.
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
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
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