Tolvaptan for Patients With Acute Neurological Injuries

September 20, 2018 updated by: Polderman, Kees, H., MD, PhD

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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

Study Type

Interventional

Enrollment (Actual)

25

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15261
        • UPMC Presbyterian
      • Pittsburgh, Pennsylvania, United States, 15219
        • Mercy Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Tolvaptan
Intervention arm. Open label, no control group
Drug: Tolvaptan
Use of Tolvaptan to treat SIADH-induced hyponatremia in selected patients with acute neurological injuries.
Other Names:
  • Samsca

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Serum sodium level
Time Frame: 1-3 days
1-3 days

Secondary Outcome Measures

Outcome Measure
Time Frame
Incidence of vasospasms
Time Frame: 3 weeks
3 weeks
Incidence of pulmonary edema
Time Frame: 2 weeks
2 weeks
Length of stay in ICU
Time Frame: 4 weeks
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Polderman, Kees, H., MD, PhD

Collaborators

University of Pittsburgh

Investigators

  • Principal Investigator: Kees Polderman, MD, PhD, University of Pittsburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2015

Primary Completion (Actual)

July 1, 2016

Study Completion (Actual)

September 1, 2016

Study Registration Dates

First Submitted

September 2, 2015

First Submitted That Met QC Criteria

September 8, 2015

First Posted (Estimate)

September 9, 2015

Study Record Updates

Last Update Posted (Actual)

September 24, 2018

Last Update Submitted That Met QC Criteria

September 20, 2018

Last Verified

September 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0002103

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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