Subarachnoid Hemorrhage, Cerebral Vasospasm
Conditions
Brief summary
Subarachnoid hemorrhage (SAH) is a devastating acute brain injury due to bleeding onto the brain surface from a ruptured aneurysm. Cerebral vasospasm (cVSP; critical narrowing of brain arteries) is a known complication after SAH and significantly increases disability and death after SAH. Vasospasm is difficult to treat and can lead to stroke. Animal studies have shown that the muscles in the artery wall play a role in cVSP. Dantrolene has been FDA approved and extensively used in clinical practice as a muscle relaxant for more than 30 years. It has been shown to provide some benefit in animal studies of cVSP, as well as in a small number of humans. However, the first human studies have only been observational and over a short period of time. This study will evaluate the safety and tolerability of intravenous dantrolene given every 6 hours over seven days to patients with or at risk for cVSP after SAH. The goal is to determine if future efficacy studies should be done to determine if treatment with Dantrolene may improve the outcome of patients with cVSP after SAH.
Detailed description
Once eligibility criteria are met, patients will be randomized to either dantrolene-IV or placebo (equiosmolar, volume-equivalent sterile water with 5% mannitol as dantrolene-IV also contains 5% mannitol). Study subjects will be visited daily by a study nurse to determine side effects, tolerability, record hemodynamic measures and laboratory values. Patients will have daily serum Na, osmolality, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALK) measured. In addition, daily bedside transcranial doppler will be performed by a blinded examiner. Patients will undergo cerebral angiograms per clinical routine. Angiographic measurements of arterial narrowing will be performed by a blinded radiologist. Specific stop criteria are pre-defined.
Interventions
DRUGDantrolene
Dantrolene 1.25mg/kg IV (includes 5% mannitol) every 6 hours x 7 days
DRUGPlacebo
equiosmolar volume (5% mannitol) every 6 hours x 7 days
Sponsors
American Heart Association
University of Massachusetts, Worcester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented aneurysmal SAH by computed tomography angiography (CTA), magnetic resonance angiography (MRA) or angiography * Secured aneurysm (coiled or clipped) * Enrollment achievable within 14 days after SAH
Exclusion criteria
* Pregnancy * Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT \>120 Units/L, AST \>120 Units/L, alkaline phosphatase \>345 Units/L (three times upper limit of normal) * Patients on verapamil * Patients with brain edema and/or elevated intracranial pressure (\>25mm Hg) * Patients treated with hypertonic saline or mannitol prior to enrollment * Patients with too severe SAH with low likelihood of survival (Hunt & Hess 5)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hyponatremia | Seven days | Number of subjects who developed hyponatremia (sNa ≤132mmol/L) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Liver Toxicity | 7 days | Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal. |
| In-hospital Mortality | up to 90 days | Number of subjects who expired during hospitalization. |
Countries
United States
Participant flow
Recruitment details
All patients with aSAH were screened for eligibility between 10/2009 and 10/2012. Inclusion criteria were aSAH ≥18 years, aneurysm fully secured by coiling or clipping, Hunt&Hess grade \<5, modified Fisher Scale \>1, ALT, AST, AlkPhos \<3x upper limit of normal, serum Na (sNa) ≥135mmol/L and no mannitol or hypertonic saline prior to drug infusion.
Pre-assignment details
Routine patient management: All aSAH patients were treated according to our institutional protocol following published aSAH critical care guidelines, including admission to our closed neuroscience intensive care unit (neuroICU) with board-certified neurointensivist as the primary attending.
Participants by arm
| Arm | Count |
|---|---|
| Dantrolene Intravenous Datrolene 1.25 mg/kg (includes 5% mannitol) every 6 hours for seven days. | 16 |
| Placebo Equiosmolar volume (5% mannitol) every 6 hours for seven days. | 15 |
| Total | 31 |
Baseline characteristics
| Characteristic | Dantrolene | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 12 | 52 years STANDARD_DEVIATION 11 | 54 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized African American | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 0 participants | 6 participants | 6 participants |
| Race/Ethnicity, Customized White | 15 participants | 9 participants | 24 participants |
| Sex: Female, Male Female | 14 Participants | 12 Participants | 26 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 16 | 1 / 15 |
| serious Total, serious adverse events | 4 / 16 | 2 / 15 |
Outcome results
Primary
Hyponatremia
Number of subjects who developed hyponatremia (sNa ≤132mmol/L)
Time frame: Seven days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dantrolene | Hyponatremia | 7 participants |
| Placebo | Hyponatremia | 10 participants |
Secondary
In-hospital Mortality
Number of subjects who expired during hospitalization.
Time frame: up to 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dantrolene | In-hospital Mortality | 2 participants |
| Placebo | In-hospital Mortality | 1 participants |
Secondary
Liver Toxicity
Number of subjects who developed liver toxicity as evidenced by Liver Function Test elevation greater than 5 times the upper limit of normal.
Time frame: 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dantrolene | Liver Toxicity | 1 participants |
| Placebo | Liver Toxicity | 0 participants |