Pharmacokinetics and Pharmacodynamics of Tissue Plasminogen Activator Administered Through an External Ventricular Drain.
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.
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada. andreas.kramer@calgaryhealthregion.ca.|Department of Clinical Neurosciences, University of Calgary, Calgary, Canada. andreas.kramer@calgaryhealthregion.ca.
Andreas H
AH
Kramer
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.|Calvin, Phoebe & Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
Craig
C
Jenne
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.|Department of Community Health Sciences, University of Calgary, Calgary, Canada.
Jessalyn K
JK
Holodinsky
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.
Stephanie
S
Todd
Department of Community Health Sciences, University of Calgary, Calgary, Canada.|Department of Surgery, University of Calgary, Calgary, Canada.
Derek J
DJ
Roberts
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.|Calvin, Phoebe & Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Canada.
Paul
P
Kubes
Department of Critical Care Medicine, University of Calgary, McCaig Tower, 3134 Hospital Drive N.W, Calgary, AB, T2N 2T9, Canada.|Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.|Department of Community Health Sciences, University of Calgary, Calgary, Canada.|Department of Medicine, University of Alberta, Alberta, Canada.
David A
DA
Zygun
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.|Department of Community Health Sciences, University of Calgary, Calgary, Canada.
Michael D
MD
Hill
University of Laval, Quebec, Canada.
Caroline
C
Leger
Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
John H
JH
Wong
D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000209:etiology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000473:pathology* / Q000601:surgery; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D006801:Humans; D007276:Injections, Intraventricular; D002532:Intracranial Aneurysm / Q000150:complications; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
D-dimer; Fibrinolysis; Intraventricular hemorrhage; Pharmacokinetics; Subarachnoid hemorrhage; Tissue plasminogen activator