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.
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.
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.
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.
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.
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]
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]
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]
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.
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.
