Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial

Locally administered tissue plasminogen activator (TPA) accelerates clearance of intraventricular hemorrhage (IVH), but its impact on neurologic outcomes remains unclear and preclinical research suggests it may have pro-inflammatory effects. We randomly allocated patients with ruptured cerebral aneurysms and IVH, treated with endovascular coiling and ventricular drainage, to receive either 2-mg intraventricular TPA or placebo every 12 hours. Cerebrospinal fluid (CSF) and serum cytokine and white blood cell (WBC) concentrations were measured before drug administration and daily for 72 hours. Cerebrospinal fluid D-dimer levels were assessed 6 and 12 hours after administration to quantify fibrinolysis. Six patients were randomized to each group. Patients treated with TPA developed higher CSF cytokine concentrations compared with placebo-treated patients (P<0.05 for tumor necrosis factor-alpha, interferon-beta, interleukin (IL)-1 alpha, IL-1 beta, IL-2, IL-4, and IL-6), as well as higher CSF WBC counts (P = 0.03). Differences were greatest after 24 hours and decreased over 48 to 72 hours. The magnitude of the inflammatory response was significantly associated with peak CSF D-dimer concentration and extent of IVH clearance. We conclude that intraventricular TPA administration produces a transient local inflammatory response, the severity of which is strongly associated with the degree of fibrinolysis, suggesting it may be induced by release of hematoma breakdown products, rather than the drug itself.