Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage

• Determine rate and variance of ventricular and cisternal clot clearance (with and without TPA). [ Time Frame: 8 Days post bleed ] [ Designated as safety issue: No ]
  In order to plan the sample size for a future "proof-of-concept" trial, we need to better define the primary endpoint (the rate of ventricular and cisternal clot clearance, as well as the degree of variance in this rate, both with and without TPA).
  
  

• Confirm the safety of intraventricular TPA. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Intrathecal TPA has been administered to many hundreds of patients world-wide, and continues to be widely used despite a paucity of strong evidence demonstrating efficacy. Thus, we believe the safety has been relatively well established. On the other hand, much of the existing data is observational and retrospective, and could therefore be vulnerable to reporting bias. Experience is more limited among patients who have been managed with endovascular coil embolization, such that our study will provide important additional safety information.
  
  
• Assess feasibility of a future multi-center trial [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  By performing a single center, prospective, randomized, double-blind, placebo-controlled trial, we will be able to (1) Estimate the recruitment rate; (2) Establish whether clinicians can be successfully blinded to treatment allocation (TPA vs. placebo); (3) Ensure that clinicians will comply with a treatment protocol
  
  

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