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.
['Kramer|Andreas H|AH|', 'Jenne|Craig|C|', 'Holodinsky|Jessalyn K|JK|', 'Todd|Stephanie|S|', 'Roberts|Derek J|DJ|', 'Kubes|Paul|P|', 'Zygun|David A|DA|', 'Hill|Michael D|MD|', 'Leger|Caroline|C|', 'Wong|John H|JH|']
D002543:Cerebral Hemorrhage D002552:Cerebral Ventricles D005260:Female D005343:Fibrinolytic Agents D006801:Humans D007276:Injections, Intraventricular D002532:Intracranial Aneurysm D008297:Male D008875:Middle Aged D010865:Pilot Projects D013345:Subarachnoid Hemorrhage D010959:Tissue Plasminogen Activator D016896:Treatment Outcome
Pharmacokinetics Tissue plasminogen activator Intraventricular hemorrhage Subarachnoid hemorrhage D-dimer Fibrinolysis