Cerebral Vasospasm After Subarachnoid Hemorrhage
Conditions
Keywords
vasospasm, subarachnoid hemorrhage, neurocritical care, dantrolene, vasorelaxation
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. Therefore, we plan to undertake this study to evaluate the safety and tolerability of treatment with dantrolene in patients with cVSP after SAH, and to determine the maximal tolerated dose to be used in future studies to determine if treatment with Dantrolene can improve the outcome of patients with cVSP after SAH.
Detailed description
Our main objectives are: 1) to evaluate the safety and tolerability of varying doses of dantrolene, by determining the treatment related adverse events, in participants with cVSP after SAH; and 2) to determine the maximal tolerated dose to be adopted in subsequent studies and 3) to determine efficacy trends of dantrolene on brain vessels as assessed by ultrasound of brain vessels (transcranial Doppler). We hypothesize that dantrolene is well-tolerated and has minimal serious adverse effects in patients with cVSP after SAH. The results can potentially bring a new treatment to patients with SAH. cVPS after SAH is a frequent cause of disability and death. A successful study demonstrating the safety of dantrolene in would be of considerable public health significance.
Interventions
DRUGDantrolene
1.25 mg/kg IV once over 60 min
Sponsors
Massachusetts General Hospital
University of Massachusetts, Worcester
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with aneurysmal SAH admitted to the Massachusetts General Hospital NeuroICU (Blake 12) and undergoing standard-of-care daily transcranial doppler (TCD). * Participants with unilateral or bilateral anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), or basilar artery vasospasm as defined by the following TCD criteria * a \>50% mean velocity increase from the baseline mean TCD velocity (baseline is the first TCD measurement, usually within 24hrs of admission), or * peak systolic TCD velocities of 200 cm/s or higher in the MCA or ACA (for MCA with a concurrent ipsilateral LR of 3.0 or higher), or peak systolic TCD velocities of 120 cm/s or higher in the PCA or basilar artery, or * any daily 100 cm/s peak systolic TCD velocity increase from the previous day, or * any longitudinal mean TCD velocity increase of 80 cm/s or more
Exclusion criteria
* Inability to obtain consent from patient or health care proxy * Age \< 18 years * Pregnancy * Traumatic SAH * Known allergy to dantrolene * Prior history of cirrhosis or hepatitis B/C, or any two of the following three liver enzymes elevated to greater than: ALT \>165 Units/L, AST \>120 Units/L, alkaline phosphatase \>345 Units/L (three times upper limit of normal) * Participants on verapamil
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | baseline until 135 minutes post-infusion | Systolic Blood Pressure (Change from baseline systolic blood pressure (pre-infusion) over time until 135 minutes post-infusion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | baseline until 135 minutes post-infusion | Mean flow velocities of vessel in vasospasm (Change from baseline mean flow velocity (pre-infusion) over time until 135 minutes post-infusion). |
| Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | baseline until 135 minutes post-infusion | Peak Systolic Velocity of vessel in vasospasm (Change from baseline peak systolic velocity (pre-infusion) over time until 135 minutes post-infusion). |
Countries
United States
Participant flow
Recruitment details
Recruitment dates: June 2007 - October 2008 Massachusetts General Hospital NeuroICU
Pre-assignment details
Participants were excluded from study if transcranial doppler (TCDs) did not show elevated velocities suggesting vasospasm. See inclusion criteria regarding specifics. After enrollment, TCDs were repeated. Once the repeat TCD confirmed elevated velocities suggestive of vasospasm, a single dose of IV dantrolene was infused.
Participants by arm
| Arm | Count |
|---|---|
| Dantrolene (Low Dose) Single dose of Dantrolene 1.25 mg/kg infused over 60 min. | 5 |
| Dantrolene (High Dose) Single dose of Dantrolene 2.5 mg/kg infused over 60 min. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Dantrolene (High Dose) | Dantrolene (Low Dose) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age Continuous | 44 years STANDARD_DEVIATION 10 | 42 years STANDARD_DEVIATION 9 | 43 years STANDARD_DEVIATION 9.5 |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 2 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 | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 1 / 5 | 0 / 5 |
Outcome results
Primary
Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
Systolic Blood Pressure (Change from baseline systolic blood pressure (pre-infusion) over time until 135 minutes post-infusion).
Time frame: baseline until 135 minutes post-infusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dantrolene (Low Dose) | Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -8 mmHg |
| Dantrolene (High Dose) | Hemodynamic Parameters (Change From Baseline Systolic Blood Pressure (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -3.4 mmHg |
Secondary
Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
Mean flow velocities of vessel in vasospasm (Change from baseline mean flow velocity (pre-infusion) over time until 135 minutes post-infusion).
Time frame: baseline until 135 minutes post-infusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dantrolene (Low Dose) | Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -18 cm/s |
| Dantrolene (High Dose) | Transcranial Doppler Mean Flow Velocity (Change From Baseline Mean Flow Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -13 cm/s |
Secondary
Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion)
Peak Systolic Velocity of vessel in vasospasm (Change from baseline peak systolic velocity (pre-infusion) over time until 135 minutes post-infusion).
Time frame: baseline until 135 minutes post-infusion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dantrolene (Low Dose) | Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -30 cm/s |
| Dantrolene (High Dose) | Transcranial Doppler Peak Systolic Velocity (Change From Baseline Peak Systolic Velocity (Pre-infusion) Over Time Until 135 Minutes Post-infusion) | -26 cm/s |