Andreas H Kramer1,2, Craig Jenne3,4, Jessalyn K Holodinsky3,5, Stephanie Todd3, Derek J Roberts5,6, Paul Kubes3,4, David A Zygun3,7,5,8, Michael D Hill7,5, Caroline Leger9, John H Wong7. 1. Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada. andreas.kramer@calgaryhealthregion.ca. 2. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. andreas.kramer@calgaryhealthregion.ca. 3. Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada. 4. Calvin, Phoebe & Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada. 5. Department of Community Health Sciences, University of Calgary, Calgary, Canada. 6. Department of Surgery, University of Calgary, Calgary, Canada. 7. Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. 8. Department of Medicine, University of Alberta, Alberta, Canada. 9. University of Laval, Quebec, Canada.
Abstract
BACKGROUND:Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity. METHODS:Twelve patients with aneurysmal SAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays. RESULTS:Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02). CONCLUSIONS: The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h.
RCT Entities:
BACKGROUND: Intraventricular hemorrhage (IVH) frequently complicates spontaneous intracerebral or subarachnoid hemorrhage (SAH). Administration of intraventricular tissue plasminogen activator (TPA) accelerates blood clearance, but optimal dosing has not been clarified. Using a standardized TPA dose, we assessed peak cerebrospinal fluid (CSF) TPA concentrations, the rate at which TPA clears, and the relationship between TPA concentration and biological activity. METHODS: Twelve patients with aneurysmalSAH and IVH, treated with endovascular coiling and ventricular drainage, were randomized to receive either 2 mg intraventricular TPA or placebo every 12 h (five doses). CT scans were performed 12, 48, and 72 h after initial administration, and blood was quantified using the SAH Sum and IVH Scores. CSF TPA and fibrin degradation product (D-dimer) concentrations were measured at baseline and 1, 6, and 12 h after the first dose using ELISA assays. RESULTS: Median CSF TPA concentrations in seven TPA-treated patients were 525 (IQR 352-2129), 323 (233-413), and 47 (29-283) ng/ml, respectively, at 1, 6, and 12 h after drug administration. Peak concentrations varied markedly (401-8398 ng/ml). Two patients still had slightly elevated levels (283-285 ng/ml) when the second dose was due after 12 h. There was no significant correlation between the magnitude of CSF TPA elevation and the rate of blood clearance or degree of D-dimer elevation. D-dimer peaked at 6 h, had declined by 12 h, and correlated strongly with radiographic IVH clearance (r = 0.82, p = 0.02). CONCLUSIONS: The pharmacokinetics of intraventricular TPA administration varies between individual patients. TPA dose does not need to exceed 2 mg. The optimal administration interval is every 8-12 h.
Authors: Neal Naff; Michael A Williams; Penelope M Keyl; Stanley Tuhrim; M Ross Bullock; Stephan A Mayer; William Coplin; Raj Narayan; Stephen Haines; Salvador Cruz-Flores; Mario Zuccarello; David Brock; Issam Awad; Wendy C Ziai; Anthony Marmarou; Denise Rhoney; Nichol McBee; Karen Lane; Daniel F Hanley Journal: Stroke Date: 2011-08-25 Impact factor: 7.914
Authors: Andreas H Kramer; Ivan Mikolaenko; Nathan Deis; Aaron S Dumont; Neal F Kassell; Thomas P Bleck; Barnett A Nathan Journal: Neurosurgery Date: 2010-10 Impact factor: 4.654
Authors: T Sasaki; T Ohta; H Kikuchi; K Takakura; M Usui; H Ohnishi; A Kondo; H Tanabe; J Nakamura; K Yamada Journal: Neurosurgery Date: 1994-10 Impact factor: 4.654
Authors: J M Zabramski; R F Spetzler; K S Lee; S M Papadopoulos; E Bovill; R S Zimmerman; J B Bederson Journal: J Neurosurg Date: 1991-08 Impact factor: 5.115