Low-Dose Recombinant Tissue-Type Plasminogen Activator Enhances Clot Resolution in Brain Hemorrhage: The Intraventricular Hemorrhage Thrombolysis Trial

Background and Purpose— Patients with intracerebral hemorrhage and intraventricular hemorrhage have a reported mortality of 50% to 80%. We evaluated a clot lytic treatment strategy for these patients in terms of mortality, ventricular infection, and bleeding safety events, and for its effect on the rate of intraventricular clot lysis. Methods— Forty-eight patients were enrolled at 14 centers and randomized to treatment with 3 mg recombinant tissue-type plasminogen activator (rtPA) or placebo. Demographic characteristics, severity factors, safety outcomes (mortality, infection, bleeding), and clot resolution rates were compared in the 2 groups. Results— Severity factors, including admission Glasgow Coma Scale, intracerebral hemorrhage volume, intraventricular hemorrhage volume, and blood pressure were evenly distributed, as were adverse events, except for an increased frequency of respiratory system events in the placebo-treated group. Neither intracranial pressure nor cerebral perfusion pressure differed substantially between treatment groups on presentation, with external ventricular device closure, or during the active treatment phase. Frequency of death and ventriculitis was substantially lower than expected and bleeding events remained below the prespecified threshold for mortality (18% rtPA; 23% placebo), ventriculitis (8% rtPA; 9% placebo), symptomatic bleeding (23% rtPA; 5% placebo, which approached statistical significance; P=0.1). The median duration of dosing was 7.5 days for rtPA and 12 days for placebo. There was a significant beneficial effect of rtPA on rate of clot resolution. Conclusions— Low-dose rtPA for the treatment of intracerebral hemorrhage with intraventricular hemorrhage has an acceptable safety profile compared to placebo and historical controls. Data from a well-designed phase III clinical trial, such as CLEAR III, will be needed to fully evaluate this treatment. Clinical Trial Registration— Participant enrollment began before July 1, 2005.

[1]  S. Mayer,et al.  Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. , 2008, The New England journal of medicine.

[2]  E. Connolly,et al.  VENTRICULOSTOMY‐RELATED INFECTIONS: A CRITICAL REVIEW OF THE LITERATURE , 2002, Neurosurgery.

[3]  S. Mayer,et al.  Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage , 2007, Stroke.

[4]  A. Algra,et al.  Applicability and relevance of models that predict short term outcome after intracerebral haemorrhage , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[5]  A David Mendelow,et al.  Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial , 2005, The Lancet.

[6]  S. Mayer,et al.  Intraventricular Thrombolysis Speeds Blood Clot Resolution: Results of a Pilot, Prospective, Randomized, Double-blind, Controlled Trial , 2004, Neurosurgery.

[7]  M. Banerjee,et al.  Brain Edema After Human Cerebral Hemorrhage A Magnetic Resonance Imaging Volumetric Analysis , 2003, Journal of neurosurgical anesthesiology.

[8]  J. Lodder,et al.  Stereotactic Treatment of Intracerebral Hematoma by Means of a Plasminogen Activator: A Multicenter Randomized Controlled Trial (SICHPA) , 2003, Stroke.

[9]  S. Haines,et al.  Fibrinolytic therapy for intraventricular hemorrhage in adults. , 2002, The Cochrane database of systematic reviews.

[10]  D. Hanley,et al.  Blood Clot Resolution in Human Cerebrospinal Fluid: Evidence of First-order Kinetics , 2001, Neurosurgery.

[11]  H. Winn,et al.  Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies , 2001, Neurology.

[12]  J. Ulatowski,et al.  Treatment of intraventricular hemorrhage with urokinase : effects on 30-Day survival. , 2000, Stroke.

[13]  H. van Loveren,et al.  Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study. , 1999, Stroke.

[14]  D. Hanley,et al.  Pharmacologic reduction of mean arterial pressure does not adversely affect regional cerebral blood flow and intracranial pressure in experimental intracerebral hemorrhage. , 1999, Critical care medicine.

[15]  S. Tuhrim,et al.  Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. , 1999, Critical care medicine.

[16]  J. Broderick,et al.  Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection. , 1999, Journal of neurosurgery.

[17]  D. Hanley,et al.  No evidence for an ischemic penumbra in massive experimental intracerebral hemorrhage , 1999, Neurology.

[18]  J. Grotta,et al.  Surgical treatment for intracerebral hemorrhage (STICH) , 1998, Neurology.

[19]  F. Diaz,et al.  A cohort study of the safety and feasibility of intraventricular urokinase for nonaneurysmal spontaneous intraventricular hemorrhage. , 1998, Stroke.

[20]  R. E. Adams,et al.  Response to external ventricular drainage in spontaneous intracerebral hemorrhage with hydrocephalus , 1998, Neurology.

[21]  G. Hankey,et al.  Surgery for primary intracerebral hemorrhage: is it safe and effective? A systematic review of case series and randomized trials. , 1997, Stroke.

[22]  J. Gilsbach,et al.  Ventricular dilatation in experimental intraventricular hemorrhage in pigs. Characterization of cerebrospinal fluid dynamics and the effects of fibrinolytic treatment. , 1997, Stroke.

[23]  J. Broderick,et al.  Early hemorrhage growth in patients with intracerebral hemorrhage. , 1997, Stroke.

[24]  J. Broderick,et al.  Volume of Intracerebral Hemorrhage: A Powerful and Easy‐to‐Use Predictor of 30‐Day Mortality , 1993, Stroke.

[25]  G. Hankey,et al.  Intracerebral hemorrhage: External validation and extension of a model for prediction of 30‐day survival , 1992, Annals of neurology.

[26]  Raul G Nogueira,et al.  Spontaneous intracerebral hemorrhage. , 1992, Neurosurgery clinics of North America.

[27]  K. Hoda,et al.  Treatment of intraventricular hemorrhage using urokinase. , 1990, Neurologia medico-chirurgica.

[28]  M. Cowan,et al.  American Heart Association. , 2018, P & T : a peer-reviewed journal for formulary management.

[29]  R. Sclabassi,et al.  Lysis of intraventricular blood clot with urokinase in a canine model: Part 3. Effects of intraventricular urokinase on clot lysis and posthemorrhagic hydrocephalus. , 1986, Neurosurgery.

[30]  R. Sclabassi,et al.  Lysis of intraventricular blood clot with urokinase in a canine model: Part 1. Canine intraventricular blood cast model. , 1986, Neurosurgery.

[31]  R. Sclabassi,et al.  Lysis of intraventricular blood clot with urokinase in a canine model: Part 2. In vivo safety study of intraventricular urokinase. , 1986, Neurosurgery.

[32]  N. Zwetnow,et al.  Quantitative Estimation of Intracerebral and Intraventricular Hematoma by Computer Tomography , 1975, Acta radiologica. Supplementum.