Brain Aneurysms: Utility of Cisternal Urokinase Irrigation

Hydrocephalus Clinical Trial

— BA&UK  

Official title:

Cerebral Aneurysms: a Retrospective Study on the Experience in Our Hospital With a Comparative Analysis Between the Different Techniques Used in Its Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04792944
• Other study ID #: CEIm 17-07-2019
• Status: Completed
• Start date: January 1, 2007
• Est. completion date: December 31, 2020

Study information

• Verified date: March 2021
• Source: University of Valencia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Despite the efforts made in its treatment, aneurysmal subarachnoid haemorrhage continues to induce high mortality and morbidity rates. Today there are treatment protocols in all hospitals. The vast majority prefer, whenever possible, the endovascular route, given its lesser aggressiveness and morbidity. Although embolization prevents aneurysm' rebleeding, it does remove the subarachnoid blood clot. Therefore, it does not modify the evolution, incidence and severity of vasospasm. The idea is to carry out a 10-year retrospective study classifying patients into five groups based on the type of treatment received, analyzing the results' differences. The aim is to improve what is done as much as possible and to be able to propose potential areas for improvement. Besides, this study will be the basis of a future prospective study, prepared without the current one's biases and errors.

Description:

Aneurysmal subarachnoid hemorrhage continues to have very high morbidity and mortality rates, despite the years elapsed and repeated attempts to reduce it. Stabilizing the aneurysm by embolization or surgical clipping leaves unresolved the vasospasm, responsible for ischemic brain damage, causing neurological sequelae and cognitive impairment. It has long been known that the deoxyhemoglobin liberated from the extravasated red blood cells retained in the subarachnoid clot is the leading cause of vasospasm. Different routes have been tried to minimize its deleterious effects, such as copious lavage of the skull base cisterns, lysing the subarachnoid clot with urokinase or rtPA, administration of vitamin C, iron chelators, or superoxydodismutase-like drugs. The volume of subarachnoid hemorrhage was soon correlated with the vasospasm severity. Once this fact was known in the 1980s and 1990s, cisternal lavage was used extensively during aneurysms' surgical clipping. Clots located in the subarachnoid space were lysed with urokinase or rtPA (recombinant tissue plasminogen activator), showing positive effects, particularly evident for the most severe bleeds, those with Fisher's grades of 3 or higher. However, the introduction of embolization changed the treatment paradigm. As the craniotomy is not carried out, the cisterns are not usually washed, which controls the rebleeding but not the vasospasm. To date, we are not aware of any study that compares the effect on vasospasm of embolization versus clipping of aneurysms with lavage of the cisterns using thrombolytic agents. In the Neurosurgery Department of our Hospital, two periods can be identified in which the treatment of brain aneurysms has been carried out differently. In the first period between 2007 and 2011, the aneurysms were primarily subjected to embolization, and only if there was no indication for endovascular treatment, surgical clipping was performed. In the second period, between 2012 and 2018, they were operated on an emergency basis with clip application and the skull base cisterns washed with urokinase. Embolization was considered if the surgical clipping was judged too risky. The aim is to analyze these two periods and compare the mortality, morbidity, and vasospasm rates, the need for a cerebrospinal fluid diversion (temporary and definitive), and the final neurological and cognitive status for the different therapeutic approaches.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 247
• Est. completion date: December 31, 2020
• Est. primary completion date: December 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• >18 years of age
• harbour one or more saccular brain aneurysms
• with or without subarachnoid hemorrhage (SAH)
• multiple aneurysms

Exclusion Criteria:

• absence of brain fusiform, traumatic or mycotic aneurysms
• SAH due to other causes (trauma, anticoagulation, antiplatelet medication, arteriovenous malformation, or tumor)
• any medical, neurological, or psychiatric condition that would impair patient's evaluation
• past medical history of bleeding disorders or liver diseases altering the coagulation
• anticoagulation
• platelet count <10x109/L
• prothrombin time >15 seconds

Related Conditions & MeSH terms

• Aneurysm
• Hemorrhage
• Hydrocephalus
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal
• Vasospasm, Cerebral
• Vasospasm, Intracranial

Intervention

Drug:
• Urokinase
Washing the subarachnoid clot induced by a subarachnoid haemorrhage aneurysmal bleeding with urokinase after aneurysm clipping

Procedure:
• Endovascular treatment
Aneurysm treatment through endovascular methods
• Clipping
Surgical clipping of brain aneurysms
• External ventricular drain
Insertion of an external ventricular drain to treat acute hydrocephalus

Locations

Country	Name	City	State
Spain	Hospital General Universitario de Valencia	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
University of Valencia

Country where clinical trial is conducted

Spain, 

References & Publications (24)

Al-Mufti F, Amuluru K, Damodara N, El-Ghanem M, Nuoman R, Kamal N, Al-Marsoummi S, Morris NA, Dangayach NS, Mayer SA. Novel management strategies for medically-refractory vasospasm following aneurysmal subarachnoid hemorrhage. J Neurol Sci. 2018 Jul 15;39 — View Citation

Arakawa Y, Kikuta K, Hojo M, Goto Y, Yamagata S, Nozaki K, Hashimoto N. Milrinone reduces cerebral vasospasm after subarachnoid hemorrhage of WFNS grade IV or V. Neurol Med Chir (Tokyo). 2004 Aug;44(8):393-400; discussion 401. — View Citation

Arthur AS, Fergus AH, Lanzino G, Mathys J, Kassell NF, Lee KS. Systemic administration of the iron chelator deferiprone attenuates subarachnoid hemorrhage-induced cerebral vasospasm in the rabbit. Neurosurgery. 1997 Dec;41(6):1385-91; discussion 1391-2. — View Citation

Asano T. Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions. Crit Rev Neurosurg. 1999 Sep 24;9(5):303-318. — View Citation

Ayer RE, Zhang JH. Oxidative stress in subarachnoid haemorrhage: significance in acute brain injury and vasospasm. Acta Neurochir Suppl. 2008;104:33-41. — View Citation

Barbosa MD, Arthur AS, Louis RH, MacDonald T, Polin RS, Gazak C, Kassell NF. The novel 5-lipoxygenase inhibitor ABT-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage. Neurosurgery. 2001 Nov;49(5):1205-12; discussion 1212-3. — View Citation

Bilginer B, Onal MB, Narin F, Soylemezoglu F, Ziyal IM, Ozgen T. The effects of intravenous cilostazol and nimodipine on cerebral vasospasm after subarachnoid hemorrhage in an experimental rabbit model. Turk Neurosurg. 2009 Oct;19(4):374-9. — View Citation

Dalbayrak S, Altas M, Arslan R. The effects of timing of aneurysm surgery on vasospasm and mortality in patients with subarachnoid hemorrhage. Acta Neurol Belg. 2011 Dec;111(4):317-20. — View Citation

Ding X, Wang ZG, Wang CW, Wang YH. [Timing of treatment on the prognosis of poor-grade aneurysmal subarachnoid hemorrhage patients]. Zhonghua Yi Xue Za Zhi. 2012 Dec 4;92(45):3211-4. Chinese. — View Citation

Dorhout Mees SM, Molyneux AJ, Kerr RS, Algra A, Rinkel GJ. Timing of aneurysm treatment after subarachnoid hemorrhage: relationship with delayed cerebral ischemia and poor outcome. Stroke. 2012 Aug;43(8):2126-9. doi: 10.1161/STROKEAHA.111.639690. Epub 201 — View Citation

Findlay JM. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery. 1995 Nov;37(5):1026-7. Erratum in: Neurosurgery 1995 Nov;37(5):1026-7. — View Citation

Górski R, Zabek M, Jarmuzek P. Influence of intraoperative using of recombinant tissue plasminogen activator on the development of cerebral angiospasm after subarachnoid haemorrhage in patients with ruptured intracranial aneurysms. Neurol Neurochir Pol. 2 — View Citation

Hamada J, Mizuno T, Kai Y, Morioka M, Ushio Y. Microcatheter intrathecal urokinase infusion into cisterna magna for prevention of cerebral vasospasm: preliminary report. Stroke. 2000 Sep;31(9):2141-8. — View Citation

Handa Y, Kaneko M, Takeuchi H, Tsuchida A, Kobayashi H, Kubota T. Effect of an antioxidant, ebselen, on development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates. Surg Neurol. 2000 Apr;53(4):323-9. — View Citation

Hänggi D, Steiger HJ. The influence of cisternal and ventricular lavage on cerebral vasospasm in patients suffering from subarachnoid hemorrhage: analysis of effectiveness. Acta Neurochir Suppl. 2011;110(Pt 2):95-8. doi: 10.1007/978-3-7091-0356-2_17. — View Citation

Hirashima Y, Endo S, Horie Y, Kurimoto M. Indications for cisternal irrigation with urokinase in postoperative patients with aneurysmal subarachnoid haemorrhage. Br J Neurosurg. 1996 Oct;10(5):477-81. — View Citation

Hosoda K, Fujita S, Kawaguchi T, Shose Y, Hamano S, Iwakura M. Effect of clot removal and surgical manipulation on regional cerebral blood flow and delayed vasospasm in early aneurysm surgery for subarachnoid hemorrhage. Surg Neurol. 1999 Jan;51(1):81-8. — View Citation

Inagawa T, Yamamoto M, Kamiya K. Effect of clot removal on cerebral vasospasm. J Neurosurg. 1990 Feb;72(2):224-30. — View Citation

Jito J, Nakasu Y, Nakasu S, Hatsuda N, Matsuda M. Tissue plasminogen activator levels after single intracisternal injection in patients with subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 2004 Feb;44(2):55-60; discussion 60. — View Citation

Kajimoto Y, Ohta T, Kuroiwa T. Comparison of intrathecally administered urokinase, tissue-type plasminogen activator, and combination of urokinase and lysine-plasminogen for clot lysis after experimental subarachnoid hemorrhage in dogs. Neurosurgery. 1997 — View Citation

Kawakami M, Kodama N, Toda N. Suppression of the cerebral vasospastic actions of oxyhemoglobin by ascorbic acid. Neurosurgery. 1991 Jan;28(1):33-9; discussion 39-40. — View Citation

Kodama N, Matsumoto M, Sasaki T, Konno Y, Sato T. Cisternal irrigation therapy with urokinase and ascorbic acid for prevention of vasospasm. Acta Neurochir Suppl. 2001;77:171-4. — View Citation

Li YH, Guo K, Zi XH, Song Z. [Combining exchange of cerebrospinal fluid with small dose of urokinase injection for subarachnoid hemorrhage]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2005 Apr;30(2):217-20. Chinese. — View Citation

Macdonald RL, Weir BK. A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke. 1991 Aug;22(8):971-82. Review. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Vasospasm	Presence and severity of vasospasm	21 days
Primary	Cerebrospinal fluid diversion	Need for temporary or definitive cerebrospinal fluid diversion	1 year
Primary	Mortality rate	Mortality rate in each group of patients	1 year
Primary	Outcome	Glasgow Outcome Score (GOSE) at discharge, 6 and 12 months posttreatment	1 year
Secondary	Aneurysm regrowth	Aneurysm regrowth on follow-up after each tipe of treatment	10 years
Secondary	Aneurysm rebleed	Aneurysm rebleed on follow-up after each tipe of treatment	10 years