Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage
Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage
The proposed study is to evaluate the acceleration the clearance of intraventricular blood
 (IVH) and subarachnoid hemorrhage (SAH) following ruptured intracranial aneurysms, thereby
 ameliorating complications, such as cerebral vasospasm, hydrocephalus and intracranial
 hypertension.

 The primary objectives are:

 1. Estimate the rate and variance of hematoma clearance following aneurysmal SAH, thereby
 facilitating sample size determination for a subsequent larger study;

 2. Assess the feasibility of a randomized controlled trial of intraventricular tissue
 plasminogen activator (TPA) among patients with SAH (enrollment rate, ability to blind
 investigators, protocol compliance);

 3. Confirm the safety of intraventricular TPA.
Outcome Measures:

 Safety will be assessed through adverse events, hemorrhagic complications and the development
 of ventriculostomy-related infections.

 The volume and clearance of intracranial blood will be determined (in ml) using computerized
 software, as well as validated semi-quantitative ordinal scales (SAH Sum Score, Modified
 Graeb Score). The amount of IVH and SAH will be assessed at baseline (day 0), 72 hours after
 treatment onset, and on post-SAH day 8.

 Additional secondary outcomes will include:

 1. The occurrence of vasospasm, as determined using transcranial Doppler ultrasonography

 2. The occurrence of radiographic vasospasm, using CT angiography.

 3. The occurrence of "clinical" (symptomatic) vasospasm

 4. The rate of catheter-related central nervous system infections

 5. Levels of cytokines, endothelin and matrix metalloproteases in cerebrospinal fluid (CSF)
 and plasma

 6. Levels of fibrin-derived products (FDP), TPA and plasminogen-activator inhibitor in CSF

 7. Levels of S100β and neuron-specific enolase (NSE) in CSF and serum

 8. Intracranial pressure

 9. Volume of CSF drainage

 10. Extended Glasgow Outcome Scale, modified Rankin scale, EuroQOL at 6 months post-SAH

 11. Duration that ventriculostomy is required; need for permanent shunt

 12. Fever burden
Inclusion Criteria:

 -  Adult patients (> 18 years old) with a proven ruptured cerebral aneurysm

 -  Aneurysm has been / will be treated with coil embolization

 -  EVD has been / will be placed as part of routine care

 -  Modified Fisher score is 4 (cisternal blood > 1 mm thick with concomitant IVH)

 -  CT scan after EVD placement shows "stability" with no increase in the amount of
 intracranial blood (Note: there is sometimes layering of blood, especially in the
 occipital horns of the lateral ventricles, that develops during the first 24-48 hours
 after a ruptured aneurysm due to circulation of blood in the CSF - this does not
 necessarily constitute an exclusion criterion).

 -  Study drug can be administered within 72 hours of the time of SAH.

 Exclusion Criteria:

 -  Concern expressed by endovascular neurosurgeon / interventional radiologist that
 aneurysm has only been incompletely treated / isolated by coil embolization.

 -  Patient requires craniotomy and clipping of the culprit aneurysm.

 -  CT scan performed post-EVD insertion OR post-coiling shows increase in amount of
 intracranial blood.

 -  Uncorrected coagulation disturbance (INR > 1.5, PTT > 45); correction is permitted (if
 coagulation disturbance develops during the study, subsequent doses of TPA should
 simply be withheld until coagulation can be corrected).

 -  Uncorrected thrombocytopenia (platelets < 50,000); correction with platelet
 transfusions is permitted.

 -  Involvement in another clinical trial

 -  Uncontrolled active internal hemorrhage

 -  Known allergy to study drug

 -  Patient is pregnant

 -  Any other condition the investigator believes would place the subject at risk if
 included in the study.