Neurosurgical Review

, Volume 36, Issue 4, pp 523–531 | Cite as

Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis

  • Stephane Litrico
  • Fabien AlmairacEmail author
  • Thomas Gaberel
  • Rohan Ramakrishna
  • Denys Fontaine
  • Jacques Sedat
  • Michel Lonjon
  • Philippe Paquis
Original Article


The aim of this study was to assess the safety and efficacy of intraventricular fibrinolysis (IVF) for aneurysmal subarachnoid hemorrhage (aSAH) with severe intraventricular hemorrhage (IVH). In this randomized controlled trial, between 2005 and 2009, patients with aSAH and severe IVH were randomly assigned into two groups: one treated with external ventricular drainage (EVD) combined with intraventricular recombinant tissue plasminogen activator (rt-PA) and the second with EVD alone. The primary end-point was mortality rate within the first 30 days. We performed meta-analysis including all published articles that compared IVF + EVD to EVD alone in patients with aSAH IVH. Eleven patients were included in the rt-PA group, eight in the control group. At 30 days, mortality rate was lower in the rt-PA group (45.5 vs. 62.5 %), but results were not statistically significant (p = 0.65). Clearance of third and fourth ventricles was obtained previously in the rt-PA group (4.25 days) compared to the control group (10.67 days) (p = 0.001). There was no statistically significant difference concerning the occurrence of complications. The meta-analysis showed a better survival rate with IVF without raised statistical significance (odds ratio = 0.32 [95 % confidence interval, 0.10–1.03]). This study shows that IVF is as safe as EVD alone for aSAH with severe IVH. It accelerates blood clot resolution in the ventricular system. Mortality rate could be improved by IVF but without significant results. Because of the severity and rarity of this pathology, a multicenter study is required.

Clinical Trial Registration Information: (NCT00823485)


Intraventricular hemorrhage Subarachnoid hemorrhage Tissue plasminogen activator Fibrinolytic agents Randomized controlled trial Meta-analysis 



We wish to express our gratitude to Dr. Laligam N. Sekhar from the University of Washington Medical Center, Seattle, USA, for his prompt response to our data request. This trial was financed by the Institutional Review Board of the Nice Hospital University, France.

Conflict of interest

The authors report no conflicts of interest concerning the materials or methods used in this study or the findings specified in this paper.


  1. 1.
    Akdemir H, Selcuklu A, Pasaoglu A, Oktem IS, Kavuncu I (1995) Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase. Neurosurg Rev 18(2):95–100PubMedCrossRefGoogle Scholar
  2. 2.
    Ducruet AF, Hickman ZL, Zacharia BE, Grobelny BT, Narula R, Guo KH, Claassen J, Lee K, Badjatia N, Mayer SA, Connolly ES Jr (2010) Exacerbation of perihematomal edema and sterile meningitis with intraventricular administration of tissue plasminogen activator in patients with intracerebral hemorrhage. Neurosurgery 66(4):648–655. doi: 10.1227/01.NEU.0000360374.59435.60 PubMedCrossRefGoogle Scholar
  3. 3.
    Findlay JM, Grace MG, Weir BK (1993) Treatment of intraventricular hemorrhage with tissue plasminogen activator. Neurosurgery 32(6):941–947, discussion 947PubMedCrossRefGoogle Scholar
  4. 4.
    Findlay JM, Jacka MJ (2004) Cohort study of intraventricular thrombolysis with recombinant tissue plasminogen activator for aneurysmal intraventricular hemorrhage. Neurosurgery 55(3):532–537, discussion 537–538PubMedCrossRefGoogle Scholar
  5. 5.
    Gaberel T, Magheru C, Parienti JJ, Huttner HB, Vivien D, Emery E (2011) Intraventricular fibrinolysis versus external ventricular drainage alone in intraventricular hemorrhage: a meta-analysis. Stroke 42(10):2776–2781. doi: 10.1161/STROKEAHA.111.615724 PubMedCrossRefGoogle Scholar
  6. 6.
    Graeb DA, Robertson WD, Lapointe JS, Nugent RA, Harrison PB (1982) Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and prognosis. Radiology 143(1):91–96PubMedGoogle Scholar
  7. 7.
    Hanley DF (2009) Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 40(4):1533–1538. doi: 10.1161/STROKEAHA.108.535419 PubMedCrossRefGoogle Scholar
  8. 8.
    Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. Lancet 1(7905):480–484PubMedCrossRefGoogle Scholar
  9. 9.
    Mayfrank L, Hutter BO, Kohorst Y, Kreitschmann-Andermahr I, Rohde V, Thron A, Gilsbach JM (2001) Influence of intraventricular hemorrhage on outcome after rupture of intracranial aneurysm. Neurosurg Rev 24(4):185–191PubMedCrossRefGoogle Scholar
  10. 10.
    Morgan T, Awad I, Keyl P, Lane K, Hanley D (2008) Preliminary report of the clot lysis evaluating accelerated resolution of intraventricular hemorrhage (CLEAR-IVH) clinical trial. Acta Neurochir Suppl 105:217–220PubMedCrossRefGoogle Scholar
  11. 11.
    Naff N, Williams MA, Keyl PM, Tuhrim S, Bullock MR, Mayer SA, Coplin W, Narayan R, Haines S, Cruz-Flores S, Zuccarello M, Brock D, Awad I, Ziai WC, Marmarou A, Rhoney D, McBee N, Lane K, Hanley DF Jr (2011) Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke 42(11):3009–3016. doi: 10.1161/STROKEAHA.110.610949 PubMedCrossRefGoogle Scholar
  12. 12.
    Naff NJ, Hanley DF, Keyl PM, Tuhrim S, Kraut M, Bederson J, Bullock R, Mayer SA, Schmutzhard E (2004) Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective, randomized, double-blind, controlled trial. Neurosurgery 54(3):577–583, discussion 583–574PubMedCrossRefGoogle Scholar
  13. 13.
    Nieuwkamp DJ, de Gans K, Rinkel GJ, Algra A (2000) Treatment and outcome of severe intraventricular extension in patients with subarachnoid or intracerebral hemorrhage: a systematic review of the literature. J Neurol 247(2):117–121PubMedCrossRefGoogle Scholar
  14. 14.
    O'Kelly CJ, Kulkarni AV, Austin PC, Urbach D, Wallace MC (2009) Shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage: incidence, predictors, and revision rates. Clinical article. J Neurosurg 111(5):1029–1035. doi: 10.3171/2008.9.JNS08881 PubMedCrossRefGoogle Scholar
  15. 15.
    Rainov NG, Burkert WL (1995) Urokinase infusion for severe intraventricular haemorrhage. Acta Neurochir (Wien) 134(1–2):55–59CrossRefGoogle Scholar
  16. 16.
    Ramakrishna R, Sekhar LN, Ramanathan D, Temkin N, Hallam D, Ghodke BV, Kim LJ (2010) Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery 67(1):110–117. doi: 10.1227/01.NEU.0000370920.44359.91, discussion 117PubMedCrossRefGoogle Scholar
  17. 17.
    Rohde V, Schaller C, Hassler WE (1995) Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage. J Neurol Neurosurg Psychiatry 58(4):447–451PubMedCrossRefGoogle Scholar
  18. 18.
    Rosen DS, Macdonald RL, Huo D, Goldenberg FD, Novakovic RL, Frank JI, Rosengart AJ (2007) Intraventricular hemorrhage from ruptured aneurysm: clinical characteristics, complications, and outcomes in a large, prospective, multicenter study population. J Neurosurg 107(2):261–265. doi: 10.3171/JNS-07/08/0261 PubMedCrossRefGoogle Scholar
  19. 19.
    S.F.A.R. (2004) Hémorragie sous-arachnoidienne grave. Conférence d'experts. Société Française d'Anesthésie et de Réanimation, ParisGoogle Scholar
  20. 20.
    Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 63(8):834–840. doi: 10.1016/j.jclinepi.2010.02.005 PubMedCrossRefGoogle Scholar
  21. 21.
    Shen PH, Matsuoka Y, Kawajiri K, Kanai M, Hoda K, Yamamoto S, Nishimura S (1990) Treatment of intraventricular hemorrhage using urokinase. Neurol Med Chir (Tokyo) 30(5):329–333CrossRefGoogle Scholar
  22. 22.
    Staykov D, Huttner HB, Struffert T, Ganslandt O, Doerfler A, Schwab S, Bardutzky J (2009) Intraventricular fibrinolysis and lumbar drainage for ventricular hemorrhage. Stroke 40(10):3275–3280. doi: 10.1161/STROKEAHA.109.551945 PubMedCrossRefGoogle Scholar
  23. 23.
    Staykov D, Wagner I, Volbers B, Huttner HB, Doerfler A, Schwab S, Bardutzky J (2011) Dose effect of intraventricular fibrinolysis in ventricular hemorrhage. Stroke 42(7):2061–2064. doi: 10.1161/STROKEAHA.110.608190 PubMedCrossRefGoogle Scholar
  24. 24.
    Todo T, Usui M, Takakura K (1991) Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase. J Neurosurg 74(1):81–86. doi: 10.3171/jns.1991.74.1.0081 PubMedCrossRefGoogle Scholar
  25. 25.
    Varelas PN, Rickert KL, Cusick J, Hacein-Bey L, Sinson G, Torbey M, Spanaki M, Gennarelli TA (2005) Intraventricular hemorrhage after aneurysmal subarachnoid hemorrhage: pilot study of treatment with intraventricular tissue plasminogen activator. Neurosurgery 56(2):205–213, discussion 205–213PubMedCrossRefGoogle Scholar
  26. 26.
    Webb AJ, Ullman NL, Mann S, Muschelli J, Awad IA, Hanley DF (2012) Resolution of intraventricular hemorrhage varies by ventricular region and dose of intraventricular thrombolytic: The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Program. Stroke. doi: 10.1161/STROKEAHA.112.650523 Google Scholar
  27. 27.
    Yepes M, Roussel BD, Ali C, Vivien D (2009) Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic. Trends Neurosci 32(1):48–55. doi: 10.1016/j.tins.2008.09.006 PubMedCrossRefGoogle Scholar
  28. 28.
    Yusuf S, Peto R, Lewis J, Collins R, Sleight P (1985) Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27(5):335–371PubMedCrossRefGoogle Scholar
  29. 29.
    Zacharia BE, Hickman ZL, Grobelny BT, DeRosa P, Kotchetkov I, Ducruet AF, Connolly ES Jr (2010) Epidemiology of aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 21(2):221–233. doi: 10.1016/ PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Stephane Litrico
    • 1
  • Fabien Almairac
    • 1
    • 6
    Email author
  • Thomas Gaberel
    • 2
    • 3
  • Rohan Ramakrishna
    • 5
  • Denys Fontaine
    • 1
  • Jacques Sedat
    • 4
  • Michel Lonjon
    • 1
  • Philippe Paquis
    • 1
  1. 1.Department of NeurosurgeryUniversity Hospital of Nice, Hôpital PasteurNiceFrance
  2. 2.Department of NeurosurgeryUniversity Hospital of CaenCaenFrance
  3. 3.INSERM U919, Sérine Protease and Pathophysiology of the Neurovascular Unit, SP2U, UMR CNRS 6232, Centre d’Imagerie et de Neurosciences Appliquées aux Pathologies, GIP CyceronUniversity Caen Lower NormandyCaenFrance
  4. 4.Department of NeuroradiologyUniversity Hospital of Nice, Hôpital St RochNiceFrance
  5. 5.Department of Neurological SurgeryUniversity of WashingtonSeattleUSA
  6. 6.Department of NeurosurgeryCHU de Nice, Hôpital PasteurNiceFrance

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