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Erschienen in: Neurocritical Care 2/2014

01.10.2014 | Original Article

Intraventricular Tissue Plasminogen Activator in Subarachnoid Hemorrhage Patients: A Prospective, Randomized, Placebo-Controlled Pilot Trial

verfasst von: Andreas H. Kramer, Derek J. Roberts, Jessalyn Holodinsky, Stephanie Todd, Michael D. Hill, David A. Zygun, Peter Faris, John H. Wong

Erschienen in: Neurocritical Care | Ausgabe 2/2014

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Abstract

Background

The quantity of subarachnoid (SAH) and intraventricular hemorrhage (IVH) occurring in the setting of a ruptured cerebral aneurysm is strongly associated with subsequent complications and poor outcomes.

Methods

We randomly allocated aneurysmal SAH patients with a modified Fisher score of 4, who had been treated with endovascular coil embolization and ventricular drainage, to receive either 2 mg intraventricular tissue plasminogen activator (TPA) every 12 h (maximum 10 mg) or placebo. Computed tomography scans were performed 12, 48, and 72 h after administration. Primary outcomes included feasibility (enrollment and consent rates), safety (assessed by prospectively screening for complications), and rate of intracranial blood clearance (measured using sequential IVH, modified Graeb, and SAH sum scores). Secondary outcomes included angiographic vasospasm, delayed cerebral ischemia, need for ventriculoperitoneal shunting, and 6-month neurological outcomes.

Results

Seventy-seven patients were screened, 17 were eligible, and 12 were randomized. The consent rate was 87 %. There were no cases of new intracranial hemorrhage complicating use of TPA. Models fit using generalized estimating equations demonstrated more rapid reduction in IVH volume (p = 0.009), modified Graeb score (p < 0.001), and SAH sum score (p < 0.001) among patients treated with TPA. SAH clearance at 48 h was enhanced by earlier drug administration (p = 0.02). There were no differences in secondary outcomes.

Conclusions

Intraventricular TPA accelerates clearance of SAH and IVH, especially when administered early. A larger-scale clinical trial of intraventricular TPA is feasible, will need to be conducted at multiple centers, and is required to determine whether this practice reduces complications and improves outcomes.
Literatur
1.
Zurück zum Zitat Fegin VL, Lawes CMM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69.CrossRef Fegin VL, Lawes CMM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69.CrossRef
2.
Zurück zum Zitat Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8.PubMedCrossRef Mayer SA, Kreiter KT, Copeland D, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59:1750–8.PubMedCrossRef
3.
Zurück zum Zitat Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21.PubMedCrossRef Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:2315–21.PubMedCrossRef
4.
Zurück zum Zitat Germanwala AV, Huang J, Tamargo RJ. Hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21:263–70.PubMedCrossRef Germanwala AV, Huang J, Tamargo RJ. Hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am. 2010;21:263–70.PubMedCrossRef
5.
Zurück zum Zitat Kramer AH, Mikolaenko I, Deis N, Dumont AS, Kassell NF, Bleck TP, Nathan B. Intraventricular hemorrhage volume predicts poor outcomes but not delayed ischemic neurological deficits among patients with ruptured cerebral aneurysms. Neurosurgery. 2010;67:1044–52.PubMedCrossRef Kramer AH, Mikolaenko I, Deis N, Dumont AS, Kassell NF, Bleck TP, Nathan B. Intraventricular hemorrhage volume predicts poor outcomes but not delayed ischemic neurological deficits among patients with ruptured cerebral aneurysms. Neurosurgery. 2010;67:1044–52.PubMedCrossRef
6.
Zurück zum Zitat Ko SB, Choi HA, Carpenter AM, et al. Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 2011;42:559–72.CrossRef Ko SB, Choi HA, Carpenter AM, et al. Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. Stroke. 2011;42:559–72.CrossRef
7.
Zurück zum Zitat Reilly C, Amidei C, Tolentino J, Jahromi BS, Macondald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2007;101:255–61.CrossRef Reilly C, Amidei C, Tolentino J, Jahromi BS, Macondald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg. 2007;101:255–61.CrossRef
8.
Zurück zum Zitat Kanamura K, Waga S, Sakakura M, et al. Comparative study of cisternal lavage methods for the treatment of cerebral vasospasm. In: Max Findlay J, editor. Cerebral vasospasm. Amsterdam: Elsevier Science Publishers; 1993. p. 471–473. Kanamura K, Waga S, Sakakura M, et al. Comparative study of cisternal lavage methods for the treatment of cerebral vasospasm. In: Max Findlay J, editor. Cerebral vasospasm. Amsterdam: Elsevier Science Publishers; 1993. p. 471–473.
9.
Zurück zum Zitat Findlay JM, Kassell NF, Weir BK, et al. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995;37:168–76.PubMedCrossRef Findlay JM, Kassell NF, Weir BK, et al. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995;37:168–76.PubMedCrossRef
10.
Zurück zum Zitat Hamada J, Kai Y, Morioka M, et al. Effect on cerebral vasospasm of coil embolization followed by microcatheter intrathecal urokinase infusion into the cisterna magna: a prospective randomized study. Stroke. 2003;34:2549–54.PubMedCrossRef Hamada J, Kai Y, Morioka M, et al. Effect on cerebral vasospasm of coil embolization followed by microcatheter intrathecal urokinase infusion into the cisterna magna: a prospective randomized study. Stroke. 2003;34:2549–54.PubMedCrossRef
11.
Zurück zum Zitat Hanggi D, Eicker S, Beseoglu K, et al. A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single center prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cen Eur Neurosurg. 2009;70:61–7.CrossRef Hanggi D, Eicker S, Beseoglu K, et al. A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single center prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cen Eur Neurosurg. 2009;70:61–7.CrossRef
12.
Zurück zum Zitat Kramer AH, Fletcher JJ. Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2011;14:489–99.PubMedCrossRef Kramer AH, Fletcher JJ. Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care. 2011;14:489–99.PubMedCrossRef
13.
Zurück zum Zitat Ramakrishna R, Sekhar LN, Ramanathan D, et al. Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;67:110–7.PubMedCrossRef Ramakrishna R, Sekhar LN, Ramanathan D, et al. Intraventricular tissue plasminogen activator for the prevention of vasospasm and hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;67:110–7.PubMedCrossRef
14.
Zurück zum Zitat Varelas PN, Rickert KL, Cusick J, et al. Intraventricular hemorrhage after aneurysmal subarachnoid hemorrhage: pilot study of treatment with intraventricular tissue plasminogen activator. Neurosurgery. 2005;56:205–13.PubMedCrossRef Varelas PN, Rickert KL, Cusick J, et al. Intraventricular hemorrhage after aneurysmal subarachnoid hemorrhage: pilot study of treatment with intraventricular tissue plasminogen activator. Neurosurgery. 2005;56:205–13.PubMedCrossRef
15.
Zurück zum Zitat Findlay JM, Jacka MJ. Cohort study of intraventricular thrombolysis with recombinant tissue plasminogen activator for aneurysmal intraventricular hemorrhage. Neurosurgery. 2004;55:532–7.PubMedCrossRef Findlay JM, Jacka MJ. Cohort study of intraventricular thrombolysis with recombinant tissue plasminogen activator for aneurysmal intraventricular hemorrhage. Neurosurgery. 2004;55:532–7.PubMedCrossRef
16.
Zurück zum Zitat Etiman N, Beseoglu K, Eicker SO, Turowski B, Steiger HJ, Hanggi D. Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. Stroke. 2013;44:2162–8.CrossRef Etiman N, Beseoglu K, Eicker SO, Turowski B, Steiger HJ, Hanggi D. Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. Stroke. 2013;44:2162–8.CrossRef
17.
Zurück zum Zitat Litrico S, Almairac F, Gaberel T, et al. Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis. Neurosurg Rev. 2013;36:523–30.PubMedCrossRef Litrico S, Almairac F, Gaberel T, et al. Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis. Neurosurg Rev. 2013;36:523–30.PubMedCrossRef
18.
Zurück zum Zitat Naff N, Williams MA, Keyl PM, Tuhrim S, Bullock MR, Mayer SA, et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke. 2011;42:3009–16.PubMedCrossRefPubMedCentral Naff N, Williams MA, Keyl PM, Tuhrim S, Bullock MR, Mayer SA, et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke. 2011;42:3009–16.PubMedCrossRefPubMedCentral
19.
20.
Zurück zum Zitat Kramer AH, Hehir M, Nathan B, Gress D, Dumont AS, Kassell NF, et al. A comparison of 3 radiographic scales for the prediction of delayed ischemia and prognosis following subarachnoid hemorrhage. J Neurosurg. 2008;109:199–207.PubMedCrossRef Kramer AH, Hehir M, Nathan B, Gress D, Dumont AS, Kassell NF, et al. A comparison of 3 radiographic scales for the prediction of delayed ischemia and prognosis following subarachnoid hemorrhage. J Neurosurg. 2008;109:199–207.PubMedCrossRef
21.
Zurück zum Zitat Lozier AP, Sciacca RR, Romagnoli MF, Connolly ES. Ventriculostomy-related infections: a critical review of the literature. Neurosurgery. 2002;51:170–82.PubMedCrossRef Lozier AP, Sciacca RR, Romagnoli MF, Connolly ES. Ventriculostomy-related infections: a critical review of the literature. Neurosurgery. 2002;51:170–82.PubMedCrossRef
22.
Zurück zum Zitat Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21:1156–61.PubMedCrossRef Hijdra A, Brouwers PJ, Vermeulen M, van Gijn J. Grading the amount of blood on computed tomograms after subarachnoid hemorrhage. Stroke. 1990;21:1156–61.PubMedCrossRef
23.
Zurück zum Zitat Hallevi H, Dar NS, Barreto AD, Morales MM, Martin-Schild S, Abraham AT, et al. The IVH score: a novel tool for estimating intraventricular hemorrhage volume: clinical and research implications. Crit Care Med. 2009;37:969–74.PubMedCrossRefPubMedCentral Hallevi H, Dar NS, Barreto AD, Morales MM, Martin-Schild S, Abraham AT, et al. The IVH score: a novel tool for estimating intraventricular hemorrhage volume: clinical and research implications. Crit Care Med. 2009;37:969–74.PubMedCrossRefPubMedCentral
24.
Zurück zum Zitat Morgan TC, Dawson J, Spengler D, Lees KR, Aldrich C, Mishra NK, et al. The modified Graeb score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome. Stroke. 2013;44:635–41.PubMedCrossRef Morgan TC, Dawson J, Spengler D, Lees KR, Aldrich C, Mishra NK, et al. The modified Graeb score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome. Stroke. 2013;44:635–41.PubMedCrossRef
25.
Zurück zum Zitat Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage: randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–21.PubMedCrossRef Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage: randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39:3015–21.PubMedCrossRef
26.
Zurück zum Zitat Sloan MA, Haley EC Jr, Kassell NF, Henry ML, Stewart SR, Beskin RR, et al. Sensitivity and specificity of transcranial Doppler ultrasonography in the diagnosis of vasospasm following subarachnoid hemorrhage. Neurology. 1989;39:1514–8.PubMedCrossRef Sloan MA, Haley EC Jr, Kassell NF, Henry ML, Stewart SR, Beskin RR, et al. Sensitivity and specificity of transcranial Doppler ultrasonography in the diagnosis of vasospasm following subarachnoid hemorrhage. Neurology. 1989;39:1514–8.PubMedCrossRef
27.
Zurück zum Zitat Vergouwen MDI, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies. Proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5.PubMedCrossRef Vergouwen MDI, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies. Proposal of a multidisciplinary research group. Stroke. 2010;41:2391–5.PubMedCrossRef
29.
Zurück zum Zitat Harrell FE Jr. General aspects of fitting regression models. In: Harrell Jr FE, editor. Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. New York: Springer; 2001. p. 11–40.CrossRef Harrell FE Jr. General aspects of fitting regression models. In: Harrell Jr FE, editor. Regression modeling strategies: with applications to linear models, logistic regression, and survival analysis. New York: Springer; 2001. p. 11–40.CrossRef
30.
Zurück zum Zitat Stenehjem E, Armstrong WS. Central nervous system device infections. Infect Dis Clin N Am. 2012;26:89–110.CrossRef Stenehjem E, Armstrong WS. Central nervous system device infections. Infect Dis Clin N Am. 2012;26:89–110.CrossRef
31.
Zurück zum Zitat Schade RP, Schinkel J, Roelandse FWC, et al. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. J Neurosurg. 2006;104:101–8.PubMedCrossRef Schade RP, Schinkel J, Roelandse FWC, et al. Lack of value of routine analysis of cerebrospinal fluid for prediction and diagnosis of external drainage-related bacterial meningitis. J Neurosurg. 2006;104:101–8.PubMedCrossRef
32.
Zurück zum Zitat King NK, Lai JL, Tan LB, Lee KK, Pang BC, Ng I, et al. A randomized, placebo-controlled pilot study of patients with spontaneous intraventricular hemorrhage treated with intravenous thrombolysis. J Clin Neurosci. 2012;19:961–4.PubMedCrossRef King NK, Lai JL, Tan LB, Lee KK, Pang BC, Ng I, et al. A randomized, placebo-controlled pilot study of patients with spontaneous intraventricular hemorrhage treated with intravenous thrombolysis. J Clin Neurosci. 2012;19:961–4.PubMedCrossRef
33.
Zurück zum Zitat Naff NJ, Hanley DF, Keyl PM, Tuhrim S, Kraut M, Bederson J, et al. Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective randomized, double-blind, controlled trial. Neurosurgery. 2004;54:577–83.PubMedCrossRef Naff NJ, Hanley DF, Keyl PM, Tuhrim S, Kraut M, Bederson J, et al. Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective randomized, double-blind, controlled trial. Neurosurgery. 2004;54:577–83.PubMedCrossRef
34.
Zurück zum Zitat Litrico S, Almairac F, Gaberel T, Ramakrishna R, Fontaine D, Sedat J, et al. Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis. Neurosurg Rev. 2013;36:523–30.PubMedCrossRef Litrico S, Almairac F, Gaberel T, Ramakrishna R, Fontaine D, Sedat J, et al. Intraventricular fibrinolysis for severe aneurysmal intraventricular hemorrhage: a randomized controlled trial and meta-analysis. Neurosurg Rev. 2013;36:523–30.PubMedCrossRef
35.
Zurück zum Zitat Findlay JM, Grace MG, Weir BK. Treatment of intraventricular haemorrhage with tissue plasminogen activator. Neurosurgery. 1993;32:941–7.PubMedCrossRef Findlay JM, Grace MG, Weir BK. Treatment of intraventricular haemorrhage with tissue plasminogen activator. Neurosurgery. 1993;32:941–7.PubMedCrossRef
Metadaten
Titel
Intraventricular Tissue Plasminogen Activator in Subarachnoid Hemorrhage Patients: A Prospective, Randomized, Placebo-Controlled Pilot Trial
verfasst von
Andreas H. Kramer
Derek J. Roberts
Jessalyn Holodinsky
Stephanie Todd
Michael D. Hill
David A. Zygun
Peter Faris
John H. Wong
Publikationsdatum
01.10.2014
Verlag
Springer US
Erschienen in
Neurocritical Care / Ausgabe 2/2014
Print ISSN: 1541-6933
Elektronische ISSN: 1556-0961
DOI
https://doi.org/10.1007/s12028-014-9965-z

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