title: Intraventricular fibrinolysis with tissue plasminogen activator is associated with transient cerebrospinal fluid inflammation: a randomized controlled trial.
abstract: 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-α, interferon-γ, interleukin (IL)-1α, IL-1β, 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.
authors: 1] Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada [2] Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: Andreas H
authors: AH
authors: Kramer
authors: The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors: Craig N
authors: CN
authors: Jenne
authors: 1] Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada [2] Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada [3] Department of Medicine, University of Alberta, Edmonton, Alberta, Canada [4] Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors: David A
authors: DA
authors: Zygun
authors: 1] Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada [2] Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada [3] Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
authors: Derek J
authors: DJ
authors: Roberts
authors: 1] Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada [2] Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors: Michael D
authors: MD
authors: Hill
authors: Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors: Jessalyn K
authors: JK
authors: Holodinsky
authors: Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada.
authors: Stephanie
authors: S
authors: Todd
authors: 1] Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada [2] The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors: Paul
authors: P
authors: Kubes
authors: Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors: John H
authors: JH
authors: Wong
mesh_terms: D000368:Aged; D002543:Cerebral Hemorrhage / Q000134:cerebrospinal fluid / Q000188:drug therapy; D016207:Cytokines / Q000134:cerebrospinal fluid; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000134:cerebrospinal fluid; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid / Q000139:chemically induced; D002532:Intracranial Aneurysm / Q000134:cerebrospinal fluid / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; C036309:fibrin fragment D; D010959:Tissue Plasminogen Activator