Unveiling the Impact of Intrathecal Fibrinolysis on Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials

Abstract

Objective

Aneurysmal subarachnoid hemorrhage (aSAH) poses a significant challenge in neurological emergencies, demanding effective therapeutic interventions to improve patient outcomes. Intrathecal fibrinolysis has emerged as a potential intervention to promote the resolution of blood clots within the subarachnoid space. within the subarachnoid space.

Methods

Extensive literature searches identified relevant RCTs exploring intrathecal fibrinolysis for aSAH management. Data extraction included study characteristics, the quality assessment of the study, and primary outcomes: delayed ischemic neurological deficit (delayed ischemic neurological deficit (DIND)) occurrence and poor neurological recovery (defined by GOS 1–3 or mRS 3–6). Along with the complications and drug preferences.

Results

9 RCTs were included in this meta-analysis. The majority of the RCTs demonstrate the promising effect of intrathecal fibrinolysis. Intracisternal fibrinolysis was found to significantly diminish the incidence of delayed ischemic neurological deficit (DIND) (RR, 0.54; 95% CI, 0.32–0.91) and poor neurological recovery (defined by GOS 1–3 or mRS 3–6) events (RR, 0.65; 95% CI, 0.47–0.90). The significant impact in delayed ischemic neurological deficit (DIND) events also showed in the subgroup analysis along with urokinase administration (RR, 0.31; 95% CI, 0.16–0.62). While intraventricular fibrinolysis did not achieve statistical significance for the primary outcomes, overall findings suggested a beneficial effect considering the choice of drugs administered.

Conclusion

This comprehensive meta-analysis highlights the potential benefits of intrathecal fibrinolysis in reducing delayed ischemic neurological deficit (DIND) occurrence and improving neurological recovery in aSAH patients. The promising results with intracisternal fibrinolysis and urokinase administration warrant further consideration in treatment protocols. Our findings contribute valuable insights, guiding evidence-based clinical decision-making and promoting advancements in aSAH management.

 

Scroll to top

Resumo

Objetivo

A hemorragia subaracnoide aneurismática (aSAH) representa um grande desafio nas emergências neurológicas, exigindo intervenções terapêuticas eficazes para melhorar os desfechos dos pacientes. A fibrinólise intratecal surge como uma estratégia para promover a resolução de coágulos sanguíneos no espaço subaracnoide.

Métodos

Pesquisas extensivas na literatura identificaram ECRs (Ensaios Clínicos Randomizados) relevantes que exploram a fibrinólise intratecal no manejo da aSAH. A extração de dados incluiu as características dos estudos, avaliação da qualidade e os desfechos primários: ocorrência de déficit neurológico isquêmico tardio (delayed ischemic neurological deficit (DIND)) e recuperação neurológica ruim, além das complicações e preferências de medicamentos.

Resultados

Nove ECRs foram incluídos nesta meta-análise. A maioria dos ECRs demonstra o efeito promissor da fibrinólise intratecal. A fibrinólise intracisternal mostrou-se significativamente eficaz na redução da incidência de delayed ischemic neurological deficit (DIND) (RR, 0,54; IC 95%, 0,32–0,91) e de eventos de recuperação neurológica ruim (RR, 0,65; IC 95%, 0,47–0,90). O impacto significativo nos eventos de delayed ischemic neurological deficit (DIND) também foi evidenciado na análise de subgrupos com a administração de uroquinase (RR, 0,31; IC 95%, 0,16–0,62). Embora a fibrinólise intraventricular não tenha alcançado significância estatística nos desfechos primários, os achados gerais sugerem um efeito benéfico considerando a escolha dos medicamentos administrados.

Conclusão

Esta meta-análise abrangente destaca os potenciais benefícios da fibrinólise intratecal na redução da ocorrência de delayed ischemic neurological deficit (DIND) e na melhora da recuperação neurológica em pacientes com aSAH. Os resultados promissores com a fibrinólise intracisternal e a administração de uroquinase justificam maior consideração nos protocolos de tratamento. Nossos achados contribuem com insights valiosos, orientando a tomada de decisões clínicas baseadas em evidências e promovendo avanços no manejo da aSAH.

 

Scroll to top

Keywords

subarachnoid hemorrhage - intracisternal fibrinolysis - intraventricular fibrinolysis - delayed ischemic neurological deficit - plasminogen activators

Palavras-chave

hemorragia subaracnoide - fibrinólise intracisternal - fibrinólise intraventricular - déficit neurológico isquêmico tardio - ativadores de plasminogênio

Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) represents a significant challenge in neurological emergencies related to sudden and often intracranial bleeding resulting from the rupture of an intracranial aneurysm.[1] [2] [3] Despite significant advancements in neurocritical care, managing aSAH continues to pose significant challenges in an evolving field, with the potential for devastating neurological sequelae.[4] [5]

One promising therapeutic approach for aSAH is intrathecal fibrinolysis, a therapeutic approach targeted at dissolving intracranial blood clots by administering fibrinolytic agents within the subarachnoid space.[6] This procedure offers a localized and direct impact of addressing the clot burden, potentially mitigating the cascading events that lead to delayed ischemic neurological deficits (delayed ischemic neurological deficit (DIND)) and poor neurological outcomes, which continue to afflict a substantial proportion of aSAH patients.[6] [7]

As neuro-interventional medicine has developed, it also has the utilization of intrathecal fibrinolysis, resulting in interest in its efficacy, safety profile, and role in shaping the clinical landscape of aSAH management.[8] [9] Integrating randomized controlled trials (RCTs) and their systematic evaluation provides a vital view to assess the evidence, offering insights that can guide clinical decision-making and refine treatment paradigms.

This paper explores the topic of intrathecal fibrinolysis in the context of aSAH, considering the historical background, pathophysiology, mechanism of action, and available clinical data. It examines the impact of intrathecal fibrinolysis on outcomes such as delayed ischemic neurological deficits DIND and neurological recovery, while also addressing complications and drug-related considerations through a review of RCTs.

The objective of this paper is to summarize the findings of recent studies, highlighting the potential benefits and limitations of intrathecal fibrinolysis in aSAH management. The analysis aims to support evidence-based clinical decision-making and contribute to improving care and outcomes for this serious neurological condition.

 

Scroll to top

Methods

Literature Search Strategy

A comprehensive literature search was conducted using PubMed, ScienceDirect, and Google Scholar to identify RCTs evaluating the use of intrathecal fibrinolysis in patients with an aneurysmal subarachnoid hemorrhage (aSAH). The search strategy included combinations of keywords and Boolean operators such as “subarachnoid hemorrhage,” “intrathecal fibrinolysis,” “intracisternal fibrinolysis,” “intraventricular fibrinolysis,” “urokinase,” “tissue plasminogen activator,” and “plasminogen activators” (e.g., “subarachnoid hemorrhage” AND “urokinase”). The research included studies published up to December 2023 without restriction on publication year or language following the PRISMA guideline ([Fig. 1]). Reference lists of included articles and relevant reviews were also manually screened to identify additional eligible studies.

Fig. 1 Literature search and studies inclusion strategy.

 

Scroll to top

Inclusion and Exclusion Criteria

Regarding inclusion, studies were obligated to be eligible for the following criteria: (1) The study population consisted of patients with aSAH. (2) The intervention including intracisternal or intraventricular fibrinolysis (3) The primary outcomes were focused on DIND and GOS scores based on the modified Rankin Scale (mRS) score (4) The secondary outcomes of interest included assessing the fibrinolytic preferences and the complications (hydrocephalus, vasospasms, hemorrhagic, mortality. (5) The study design had to be randomized controlled trials.

 

Scroll to top

Data Collection and Quality Assessment

[Fig. 2]. assesses the included studies' quality based on the Cochrane Risk of Bias (ROB) tools. Data extraction was done to provide the characteristics of the studies. Several vital outcomes were included, such as delayed ischemic neurological deficits. Vasospasms hydrocephalus and unfavorable outcomes following a Glasgow Outcome Scale score ranging from 1 to 3 and a Modified Rankin Score between 3 and 6. Secondary outcome data were collected to calculate individual and combined risk ratios (RR) and use 95% confidence intervals (CIs).

Fig. 2 Quality assessment of the studies included using the risk of bias Cochrane's Collaboration tools.

 

Scroll to top

 

Scroll to top

Results

We found 9 articles of RCTs that can be included in this study and analysis. All the 9 studies were assessed with RoB tools to assess the quality of the studies. The majority of the 9 studies provided a relatively high score for the criteria. This suggests that the studies included generally carried a low risk of bias. The characteristics of the studies included can be seen in [Table 1].

Table 1 Characteristics of the RCTs included in this analysis

Study	Year	Country	RCTs design	Total Patients		Male (%)	Fisher Grade 3–4 (%)	Clipping (%)	Thrombolytics	Timing	Delivery
				Intervention	Control
Findlay et al[23]	1995	Canada	Multi center	51	49	50	NR	100	rt-Pa	Intraoperative	IC
Hamada et al[24]	2003	Japan	Multi center	53	57	34.5	87.3	0	UK	Postoperative	IC
Li et al[25]	2005	China	Single center	68	66	72.4	NR	NR	UK	Postoperative	IC
Hanggi et al[26]	2009	Germany	Single center	9	11	45	100	60	UK	Postoperative	IC
Yamamoto et al[15]	2010	Japan	Single center	20	20	35	87.5	100	TK	Postoperative	IC
Litrico et al[27]	2013	France	Single center	11	8	60	NR	60	rt-Pa	Postoperative	IV
Etminan et al[28]	2013	Germany	Single center	30	30	36.7	96.7	5.3	rt-Pa	Postoperative	IV
Kramer et al[17]	2014	Canada	Single center	6	6	25	100	0	tPa	Postoperative	IV
Eicker et al[29]	2012	Germany	Single center	16	19	48.6	100	59.1	rt-Pa	Postoperative	IV

Abbreviations: IC, intracisternal fibrinolysis; IV, intraventricular fibrinolysis; NR, not reported; urokinase, urokinase; tisokinase, Tisokinase; rtPA, recombinant type plasminogen activator; RCTs, randomized controlled trials.

Results regarding the DIND and poor neurological recovery (defined by GOS 1–3 or mRS 3–6) events analysis can be found in [Fig. 3]. The analysis of RCTs included in our study indicates that, overall, intracisternal fibrinolysis significantly reduces the occurrence of either DIND (RR, 0.54;95% CI, 0.32–0.91), p = 0.07, I2 = 51%) or poor neurological recovery (defined by GOS 1–3 or mRS 3–6) events (RR, 0.65;95% CI, 0.47–0.90), p = 0.20, I2 = 31%) compared with the control group. However, when examining both DIND (RR, 0.74;95% CI, 0.35–1.59), p = 0.21, I2 = 33%) and poor neurological recovery (defined by GOS 1–3 or mRS 3–6) events (RR, 0.77;95% CI, 0.53–1.11), p = 0.67, I2 = 0%) in studies with intraventricular fibrinolysis, our study indicates that it did not achieve statistical significance ([Fig. 4]).

Fig. 3 Meta-analysis of the intracisternal fibrinolytic impact compared with the control group regarding (A) delayed ischemic neurological deficit (DIND) incidence and (B) poor neurological recovery (defined by GOS 1–3 or mRS 3–6).

Fig. 4 Meta-analysis of the intraventricular fibrinolytic impact compared with the control group in terms of (A) delayed ischemic neurological deficit (DIND) incidence and (B) poor neurological recovery (defined by GOS 1–3 or mRS 3–6).

The analysis of the intrathecal fibrinolysis and DIND events stratified from the drugs administered can be seen in [Fig. 5]. Three RCTs using the urokinase as the fibrinolytic for the patients showed significant results compared with the control groups (RR, 0.31;95% CI, 0.16–0.62), p = 0.97, I2 = 0%). However, the analysis of the RCTs using tPA showed no significant impact in DIND events (RR, 0.76;95% CI, 0.52–1.12), p = 0.22, I2 = 27%). The overall findings indicate that the experimental group significantly reduces the incidence of DIND events, considering the choice of drugs administered. (RR, 0.61;95% CI, 0.41–0.91), p = 0.09, I2 = 40%).

Fig. 5 Forest plot intrathecal fibrinolysis and delayed ischemic neurological deficit (DIND) events analysis stratified from the drugs administered in the RCTs.

The analysis of complications can be seen in [Fig. 6]. vasospasm events revealed a significant difference (RR, 0.64;95% CI, 0.47–0.87, p = 0.13, I² = 34%) between patients who underwent intrathecal fibrinolysis and those who did not ([Fig. 6A]). Only one out of the nine RCTs from Eicker et al. does not favor intrathecal fibrinolysis. Regarding the incidence of hydrocephalus, intrathecal fibrinolysis showed no significant difference. This suggests that the occurrence of hydrocephalus is comparable between the two groups, regardless of the better result shown by the intercisternal fibrinolysis RCTs (RR, 0.78;95% CI, 0.50–1.02, p = 0.38, I² = 6%). Both analyses do not show significant differences in terms of hemorrhagic and mortality. The analysis showed no proof that intrathecal fibrinolysis increased the hemorrhagic complications compared with the control group (RR, 1.40;95% CI, 0.77–2.57, p = 0.80, I² = 0%). Similar to the hemorrhagic complication, the mortality complication did not significantly separate the two groups. This finding suggests that patients with intrathecal fibrinolysis do not exhibit a decrease in overall mortality rate complication (RR, 0.67;95% CI, 0.44–1.02, p = 0.91, I² = 0%). Funnel plots of the analysis can be seen in [Supplementary Figs. S1-S4].

Fig. 6 Forest plot of the (A) vasospasm, (B) hydrocephalus, (C) hemorrhagic, (D) mortality.

 

Scroll to top

Discussion

The management of aneurysmal subarachnoid hemorrhage (aSAH) remains a complex challenge in the realm of neurocritical care. This discussion section critically interprets the findings of our comprehensive meta-analysis, focusing on intrathecal fibrinolysis, its efficacy in mitigating delayed ischemic neurological deficits DIND and improving neurological recovery, and its safety profile.

The included RCTs exhibited clinical heterogeneity in several aspects, including patient demographics, sample sizes, aneurysm severity, timing of fibrinolytic administration, and the specific fibrinolytic agents used (e.g., urokinase, rtPA, and tisokinase). These variations could influence the observed outcomes and limit the generalizability of the findings. To address this, subgroup analyses were conducted based on the route of administration (intracisternal versus intraventricular) and type of fibrinolytic agent. These subgroup results revealed that intracisternal administration and urokinase use were associated with more favorable outcomes, while intraventricular administration did not achieve statistical significance. Heterogeneity across studies was assessed using the I² statistics, with moderate heterogeneity observed in some outcomes. While I² values between 30% and 60% were considered indicative of moderate heterogeneity, consistent trends across studies suggest a potential benefit. The funnel plots of analysis can be seen in the supplementary.

Efficacy of Intrathecal Fibrinolysis

Our analysis of RCTs provides compelling evidence that intracisternal fibrinolysis significantly reduces the incidence of DIND and poor neurological recovery (defined by GOS 1–3 or mRS 3–6) in aSAH patients.[10] [11] These findings align with the concept that localized clot dissolution within the subarachnoid space may prevent or ameliorate the cerebral ischemia frequently accompanying aSAH in this meta-analysis, incorporating data from nine RCTs. DIND characterized by cerebral ischemia following SAH, is significant in morbidity and mortality.[12] [13] [14] Its underlying mechanism remains elusive, with recent research suggesting that vasospasm is not the sole culprit. Factors such as early brain injury, intravascular inflammation, and microthrombosis have also been implicated.[15] [16] Our study revealed a reduction in DIND incidence with intracisternal fibrinolysis, while no statistically significant difference was observed in the intraventricular fibrinolysis group. This divergence between intracisternal and intraventricular approaches underscores the need for a more nuanced understanding of fibrinolytic techniques and their specific mechanisms of action within the subarachnoid space.[12] [17]

 

Scroll to top

Drug-Specific Considerations

The impact of the choice of fibrinolytic agent on outcomes remains uncertain. Many thrombolytic agents employed in these investigations were tPA, rtPA, and urokinase. Notably, only one study assigned patients to either tPA or urokinase therapy, and it reported no significant differences in the effects of fibrinolysis on unfavorable neurological outcomes or DIND ischemic between patients treated with either agent.[18] [19] [20] Our subgroup analysis stratified by the choice of fibrinolytic agents provides valuable insights. The use of urokinase in intrathecal fibrinolysis demonstrated a significant reduction in DIND events, while tPA showed no significant impact. These findings suggest that the choice of fibrinolytic drug plays a critical role in the success of intrathecal fibrinolysis, emphasizing the need for further investigation into the optimal agent for this intervention.[12] [17]

 

Scroll to top

Complications and Safety

Our analysis of complications, including vasospasm, hydrocephalus, hemorrhagic events, and mortality, shows a critical safety profile of intrathecal fibrinolysis. Notably, intrathecal fibrinolysis significantly reduced the incidence of vasospasm, significantly contributing to poor outcomes in aSAH. The targeted administration of drugs into the thecal compartment obviates the need to breach the blood-brain barrier, thus expanding the array of treatment options at one's disposal. External ventricular drains (EVDs) are commonly employed in several standard hospital protocols for the monitoring of intracranial pressure (ICP). These devices serve as a simple method for the administration of medication via this route.[12] [17] [21] [22] However, the occurrence of hydrocephalus, hemorrhagic complications, and mortality did not show significant differences between the intrathecal fibrinolysis group and the control group.

These findings also align with recent research that indicated the incidence of chronic hydrocephalus requiring shunt placement after aSAH has happened up to 31.2%. Furthermore, patients who develop hydrocephalus after aSAH tend to have a less favorable prognosis than those who do not.[8]

 

Scroll to top

Clinical Implications and Future Directions

Our meta-analysis showed the potential benefits of intracisternal fibrinolysis, mainly when using urokinase, in reducing DIND and improving neurological recovery in aSAH patients. These findings have clinical implications, suggesting that intrathecal fibrinolysis may be valuable to aSAH management protocols.

However, further research is warranted to elucidate the precise mechanisms of intraventricular fibrinolysis and explore its potential benefits fully. In this study, random-effects models were used throughout the meta-analysis to account for clinical and methodological heterogeneity among the included studies. This modeling approach assumes that the true effect size may vary due to differences in patient populations, treatment protocols, and settings. Several pooled estimates demonstrated wide confidence intervals, indicating underlying variability in study results and reduced precision of the effect estimates. Consequently, while trends favoring certain interventions, such as intracisternal fibrinolysis or urokinase, were observed, these findings should be interpreted cautiously. In particular, the number of RCTs specifically evaluating urokinase was limited, reducing the strength of any direct comparison with other fibrinolytic agents like rtPA. Statements suggesting a preference for urokinase should be tempered, as the evidence remains preliminary.

 

Scroll to top

 

Scroll to top

Conclusion

In conclusion, this meta-analysis contributes valuable insights into the evolving landscape of aSAH management. While challenges persist, intrathecal fibrinolysis, especially when administered intracisternal with urokinase, might possibly be useful for managing such patients. These findings encourage ongoing research and clinical exploration to advance the care of individuals affected by this complex neurological condition.

 

Scroll to top

 

Scroll to top

Conflict of Interest

The authors report no conflict of interest.

Availability of Data and Materials

The data used and analyzed during the current study are available from the corresponding author upon reasonable request.

Authors' Contributions

JN, ARW, GAEK, TKPJ: data collection, data analysis, and manuscript preparation; JN: writing — original draft; JN, ARW, GAEK, TKPJ: copyediting, proofreading, and revision. All authors contributed to the conception and design of the study, critical revision of the manuscript, and final approval.

• References

• 1 Leclerc JL, Garcia JM, Diller MA. et al. A comparison of pathophysiology in humans and rodent models of subarachnoid hemorrhage. Front Mol Neurosci 2018; 11: 71
• 2 Sun J, Tan G, Xing W, He Z. Optimal hemoglobin concentration in patients with aneurysmal subarachnoid hemorrhage after surgical treatment to prevent symptomatic cerebral vasospasm. Neuroreport 2015; 26 (05) 263-266
• 3 Rato MJCN, Maliawan S, Niryana IW, Mahadewa TGB. Characteristics of Congenital Hydrocephalus Patients at Prof. Dr. IGNG Ngoerah General Hospital Denpasar. Neurologico Spinale Medico Chirurgico 2023; 6 (01) 6-10
• 4 Lawton MT, Vates GE. Subarachnoid Hemorrhage. N Engl J Med 2017; 377 (03) 257-266
• 5 Biller J, Godersky JC, Adams Jr HP. Management of aneurysmal subarachnoid hemorrhage. Stroke 1988; 19 (10) 1300-1305
• 6 Roelz R, Schubach F, Coenen VA. et al. Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial. Trials 2021; 22 (01) 285
• 7 Alaraj A, Charbel FT, Amin-Hanjani S. Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage. Neurol Res 2009; 31 (06) 651-659
• 8 Yang C, Li Y. Review of the prevention and treatment of hydrocephalus after aneurysmal subarachnoid hemorrhage. World Neurosurg 2022; 168: 134-138
• 9 Öhman J, Servo A, Heiskanen O. Effect of intrathecal fibrinolytic therapy on clot lysis and vasospasm in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 1991; 75 (02) 197-201
• 10 Siler DA, Gonzalez JA, Wang RK, Cetas JS, Alkayed NJ. Intracisternal administration of tissue plasminogen activator improves cerebrospinal fluid flow and cortical perfusion after subarachnoid hemorrhage in mice. Transl Stroke Res 2014; 5 (02) 227-237
• 11 Kuo LT, Huang APH. The pathogenesis of hydrocephalus following aneurysmal subarachnoid hemorrhage. Int J Mol Sci 2021; 22 (09) 5050
• 12 Zhang YP, Shields LBE, Yao TL, Dashti SR, Shields CB. Intrathecal treatment of cerebral vasospasm. J Stroke Cerebrovasc Dis 2013; 22 (08) 1201-1211
• 13 Rosengart AJ, Schultheiss KE, Tolentino J, Macdonald RL. Prognostic factors for outcome in patients with aneurysmal subarachnoid hemorrhage. Stroke 2007; 38 (08) 2315-2321
• 14 Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL. Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 2004; 101 (02) 255-261
• 15 Yamamoto T, Esaki T, Nakao Y, Mori K. Efficacy of low-dose tissue-plasminogen activator intracisternal administration for the prevention of cerebral vasospasm after subarachnoid hemorrhage. World Neurosurg 2010; 73 (06) 675-682
• 16 Amin-Hanjani S, Ogilvy CS, Barker II FG. Does intracisternal thrombolysis prevent vasospasm after aneurysmal subarachnoid hemorrhage? A meta-analysis. Neurosurgery 2004; 54 (02) 326-334 , discussion 334–335
• 17 Kramer AH, Fletcher JJ. Locally-administered intrathecal thrombolytics following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. Neurocrit Care 2011; 14 (03) 489-499
• 18 Usui M, Saito N, Hoya K, Todo T. Vasospasm prevention with postoperative intrathecal thrombolytic therapy: a retrospective comparison of urokinase, tissue plasminogen activator, and cisternal drainage alone. Neurosurgery 1994; 34 (02) 235-244 , discussion 244–245
• 19 Hariton GB, Findlay JM, Weir BKA, Kasuya H, Grace MGA, Mielke BW. Comparison of intrathecal administration of urokinase and tissue plasminogen activator on subarachnoid clot and chronic vasospasm in a primate model. Neurosurgery 1993; 33 (04) 691-696 , discussion 696–697
• 20 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; 40 (03) 572-577
• 21 Grossen AA, Ernst GL, Bauer AM. Update on intrathecal management of cerebral vasospasm: a systematic review and meta-analysis. Neurosurg Focus 2022; 52 (03) E10
• 22 Treggiari-Venzi MM, Suter PM, Romand JA. Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: a problem of neurointensive care. Neurosurgery 2001; 48 (02) 249-261 , discussion 261–262
• 23 Findlay JM. A randomized trial of intraoperative, intracisternal tissue plasminogen activator for the prevention of vasospasm. Neurosurgery 1995; 37 (05) 1026-1027
• 24 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 (11) 2549-2554
• 25 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; 30 (02) 217-220
• 26 Hänggi D, Eicker S, Beseoglu K, Behr J, Turowski B, Steiger HJ. A multimodal concept in patients after severe aneurysmal subarachnoid hemorrhage: results of a controlled single centre prospective randomized multimodal phase I/II trial on cerebral vasospasm. Cent Eur Neurosurg 2009; 70 (02) 61-67
• 27 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 (04) 523-530 , discussion 530–531
• 28 Etminan N, Beseoglu K, Eicker SO, Turowski B, Steiger HJ, Hänggi D. Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. Stroke 2013; 44 (08) 2162-2168
• 29 Eicker SO, Beseoglu K, Etminan N. et al. The effect of intraventricular thrombolysis in combination with low-frequency head motion after severe subarachnoid hemorrhage: interim analysis of safety, clot clearance rate and delayed cerebral ischemia. Springer; 2012.

Publikationsverlauf

Eingereicht: 09. Januar 2025

Angenommen: 22. Mai 2025

Artikel online veröffentlicht:
08. Oktober 2025