Neurocrit Care (2011) 15:241–246

DOI 10.1007/s12028-011-9581-0

REVIEW

Rebleeding After Aneurysmal Subarachnoid Hemorrhage

R. M. Starke • E. S. Connolly Jr. • The Participants in the International Multi-disciplinary
Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage

Published online: 15 July 2011

Ó Springer Science+Business Media, LLC 2011

Abstract Rebleeding after initial aneurysmal subarach-
noid hemorrhage (SAH) can have substantial impact on
overall patient outcome. While older studies have suggested
rebleeding occurs in about 4% of patients during the first day
after initial aneurysmal bleed, these studies may have failed
to capture very early rebleeds and, consequently, underes-
timated the impact of rebleeding. An electronic literature
search was performed to identify English-language articles
published or available for review from February 1975
through October 2010. A total of 43 articles (40 original
research and 3 review articles) focused on rebleeding after
initial aneurysmal SAH in humans were selected for review.
Although most studies supported an incidence of rebleeding
B4%, studies investigating ultra-early rebleeding reported
bleeding within the first 24 h following aneurysmal SAH
in as many as 9–17% of patients, with most cases occur-
ring within 6 h of initial hemorrhage. Overall, studies
The Participants in the International Multi-disciplinary Consensus
Conference on the Critical Care Management of Subarachnoid
Hemorrhage are Michael N. Diringer, Thomas P. Bleck, Nicolas
Bruder, E. Sander Connolly, Jr., Giuseppe Citerio, Daryl Gress,
Daniel Hanggi, J. Claude Hemphill, III, MAS, Brian Hoh, Giuseppe
Lanzino, Peter Le Roux, David Menon, Alejandro Rabinstein, Erich
Schmutzhard, Lori Shutter, Nino Stocchetti, Jose Suarez, Miriam
Treggiari, MY Tseng, Mervyn Vergouwen, Paul Vespa, Stephan
Wolf, Gregory J. Zipfel.
R. M. Starke
Department of Neurosurgery, University of Virginia
School of Medicine, Charlottesville, VA, USA
E. S. Connolly Jr. (&)
Department of Neurosurgery, Columbia University College
of Physicians and Surgeons, 710 West 168th Street, New York,
NY 10032, USA
e-mail: esc5@columbia.edu
investigating antifibrinolytic therapy to reduce rebleeding
have failed to clearly demonstrate overall therapeutic bene-
fit. Short-course antifibrinolytic therapy may have a role
prior to initial aneurysm repair, although insufficient data are
currently available.
Keywords Antifibrinolytic
Predictor

Ultra-early rebleeding
Introduction
Following aneurysmal subarachnoid hemorrhage (SAH),
the major causes of morbidity and mortality are due to the
initial hemorrhage, rebleeding, and cerebral ischemia due
to vasospasm. Mortality is reported to be as high as 80% in
patients who rebleed from their aneurysm [1]. When left
untreated or when there is a delay in treatment, the rate of
rebleeding is significant. More recent studies have found
that the incidence of rebleeding may be underestimated due
to ultra-early rebleeding during transfer or prior to initial
imaging [2–5].
This article was designed to explore both older and more
recent literature for rebleeding after SAH. Studies evaluating
the incidence of rebleeding, predictors for rebleeding, and
potentially preventive therapies were reviewed. Explana-
tions were provided to understand discrepancies in available
the literature.
Methods
An electronic Medline literature search was performed to
identify articles published or available through early view
journal features between February 1975 and October 2010.

123
242
The search was conducted using the key words ‘‘rebleeding’’
and ‘‘SAH.’’ Article titles were reviewed to select relevant
articles that discussed incidence of re-bleeding as an out-
come measure and/or prevention of rebleeding through
antifibrinolytic therapy. Abstracts of candidate articles
were reviewed for relevance if the paper was published in
English. A final selection of articles was made for inclusion
in this review after reviewing abstracts and/or full papers.
Both original research involving human subjects and
review articles were included.
Summary of the Literature
The initial search yielded 643 candidate articles. Among
these, 43 articles were identified that directly dealt with
rebleeding following aneurysmal SAH, including 40 ori-
ginal research studies [2–4, 6–42] and three review articles
[43–45]. Original research studies were generally obser-
vational studies, with 13 papers describing 11 unique
randomized trials [3, 12–14, 35–42].
Rebleeding was ascertained at different time points
among the various publications. Population samples were
also varied. The quality of the evidence supporting early
surgery to prevent rebleeding and improve outcome
appeared to be very good, with almost all the literature
supporting early surgery. Aneurysm repair during the
vasospasm period (days 4–10) is probably no better than
repair with modest delay (days 10–14) but the literature is
sparse concerning this issue. The evidence supporting a
short course of antifibrinolytic therapy (<72 h) prior to
aneurysm repair is good in so far as this appears to reduce
rebleeding. Benefits are less clear for overall outcome,
possibly due to insufficient sample sizes.
Incidence and Risk Factors for Rebleeding
Early studies published through 1990 demonstrated that,
when left untreated, the rate of rebleeding after SAH is
approximately 4% within the first 24 h, 1–2% per day over
the next 14 days, 50% during the first 6 months, and 3%
per year thereafter [7–10, 43, 44]. Since 2002, there have
been numerous reports examining the contemporary inci-
dence of re-bleeding, but the only available prospectively
collected data come from the International Cooperative
Study on the Timing of Aneurysm Surgery (ISAT) study.
Interpreting data from ISAT is limited since only about
25% of all patients with aneurysmal SAH were included
[12–14]. In the ISAT trial, the rebleeding rate was 1.7% for
patients enrolled approximately 48 h post-SAH and treated
within another 36 h. Retrospective studies report a range
from 3.2 to 25% depending on the means of ascertainment
123
Neurocrit Care (2011) 15:241–246
with a likely percentage being somewhere between 5.3 and
11.4% (Table 1).
A number of studies have suggested that the rate of
ultra-early hemorrhage is significantly underestimated.
Studies have found the incidence of re-hemorrhage in the
first 24 h following aneurysmal SAH to be as high as
9–17%, with 40–87% of early rebleeding cases occurring
within the first 6 h [2–4]. Variability in reports may reflect
a significant number of rebleeding episodes that may not
have been captured for analysis, such as those occurring
during transfer and prior to initial imaging.
Most studies assessing the incidence of rebleeding
reinforce the concept that the vast majority of rebleeding
occurs during the first 8 h, making therapeutic intervention
a major challenge. Risk factors that make rebleeding more
common include: (1) increasing aneurysm size, (2)
increasing neurological deficit, (3) angiography within 3 h
of bleeding, (4) sentinel hemorrhage, and (5) loss of con-
sciousness at initial bleed [27]. The principle risk factor for
rebleeding appears to be a history of treatment with
incomplete obliteration. The second most important risk
factor is increased time to treatment, with studies demon-
strating increased rates of bleeding with patient transfer,
delay in treatment, and inability of provide successful
treatment [3, 7, 16, 29–33, 43, 44].
Antifibrinolytic Therapy and the International
Cooperative Study on the Timing of Aneurysm Surgery
Study
The International Cooperative Study on the Timing of
Aneurysm Surgery trial presented outcome data for
patients allocated to antifibrinolytic therapy or no antifi-
brolytics, based on prognostic factors. In an analysis of
patients who underwent ‘‘early surgery’’ (<72 h), the
incidence of rebleeding was 5.6%, with 73% occurring
within the first 24 h [9, 10]. Rebleeding, therefore, occur-
red for 4.1% during the first day after SAH and 1% per day
for the first 2 weeks. Sixty-nine percent received a pro-
longed course of antifibrinolytic therapy. Cumulative
2-week rebleed rate was 11.7% with antifibrinolytic ther-
apy versus 19.4% for those not receiving antifibrinolytics;
however, antifibrinolytic therapy was associated with a
marked increase (32 vs. 23%) in the 2-week risk of delayed
cerebral ischemia (DCI). Due to the offsetting risks of
rebleeding versus DCI, there was no significant difference
in functional outcome between those that did and did not
receive antifibrinolytic therapy.
Cochrane Database on Antifibrinolytic Use
Nine trials involving 1,399 patients were included in a
Cochrane review [45]. (See Table 2.) Eight of the nine
Neurocrit Care (2011) 15:241–246 243

Table 1 Studies evaluating rebleeding as an outcome after early surgery

Reference Design Outcome

Cha et al. [17] Retrospective N = 492 8% rebleeding with 74% rebleeding within 2 h
Tong et al. [18] Retrospective patients with Hunt–Hess grade Rebleeding in 10% treated 4–10 days after initial
I–III upon admission admitted 4–10 days SAH and 8% treated 11–30 after SAH
after initial SAH N = 115
Ruigrok et al. [19] Retrospective N = 208 14% rebleeding
Molyneux et al. [13] Prospective International Subarachnoid 24 rebleeds >1 year, 13 from treated aneurysm,
Aneurysm Trial N = 2143 4 from untreated aneurysm, an 6 from de novo
aneurysm
Tanno et al. [20] Retrospective N = 5612 3% rebleeding with half rebleeding within 6 h
Hellingman et al. [21] Retrospective N = 34 Rebleeding in 21%. No increased risk with
external ventricular drainage or lumbar
punctures for acute hydrocephalus
Machiel Pleizier et al. [22] Retrospective N = 354 Rebleeding in 25%
Beck et al. [23] Retrospective N = 237 Rebleeding in 10%, 10-fold risk when sentinel
hemorrhage
Kitsuta et al. [24] Retrospective N = 202 Rebleeding in 21%, with higher risk when loss of
consciousness and hyperglycemia
Ruijs et al. [25] Retrospective patients treated with external Rebleeding in 5 of 18 patients (28%)
lumbar drainage before aneurysm repair
N = 18
Kusumi et al. [26] Retrospective N = 69 Higher rate of rebleeding when angiography
within 3 h
Naidech et al. [27] Retrospective N = 574 Rebleeding in 7%, with increased risk for poor
grade and large aneurysms
McIver et al. [28] Retrospective N = 304 Rebleeding in 5%. No increased risk when using
preoperative ventriculostomy
Molyneux et al. [12] Prospective International Subarachnoid Ranodmization occurred 48 after SAH.
Aneurysm Trial N = 2143 Rebleeding in 2% prior to treatment

Table 2 Randomized clinical trials using long-term antifibrinolytic therapy

Reference Design Outcome
Rebleeding Ischemia Death
Maximum Treatment Number AF Controls AF Controls AF Controls
time to duration AF/Control
first dose, days

Girvin [34] 7 7.7 days mean 39/27 36 15 NR NR 18 15

Van Rossum et al. [35] 14 10 days 26/25 19 16 NR NR 58 44
Chandra [36] 7 3 weeks 20/19 5 21 NR NR 5 26
Maurice-Williams [37] 4 6 weeks 25/25 24 56 NR NR 12 44
Kaste and Ramsay [38] 3 3 weeks 32/32 22 19 74 52 13 13
Fodstad et al. [39] 3 6 weeks 30/29 24 20 26 10 43 31
Vermeulen et al. [40] 3 6 weeks 241/238 9 24 24 15 35 37
Tsementzis et al. [41] 3 4 weeks 50/50 24 24 44 22 44 28
Roos [42] 4 3 weeks 229/233 19 33 30 32 5 45
AF patients treated with antifibrinolytic therapy, NR not reported

trials used tranexamic acid (TXA) (4–9 g/day) and one poor outcome or death with antifibrinolytics (TXA, epsilon
used epsilon aminocaproic acid (EACA) (24 g/day). Data aminocaproic acid, or an equivalent), despite a marked
from 1,041 patients in three trials showed no benefit on significant reduction in rebleeding. This disconnect

123
244
appeared to be a result of the significantly higher incidence
of cerebral ischemia in the treated patients. There was no
difference in incident hydrocephalus. Of note, all trials
reviewed involved treatment with antifibrinolytics during
the vasospasm period and for weeks afterward. In many of
the trials, state-of-the-art anti-vasopasm maneuvers were
not routine. Furthermore, the first dose in some of these
trials could have been administered as late as 4 days after
SAH, when rebleeding is decidedly less common. The last
study utilizing this ‘‘outmoded’’ approach was published in
2000.
Preventing Rebleeding with a Short Course
of Antifibrinolytic Therapy
Because a number of studies demonstrated that the reduced
incidence of pre-operative rebleeding is offset by an increase
in ischemic deficits when antifibrinolytic treatment is
administered for greater than 72 h, long-term use of antifi-
brinolytic therapy has largely been abandoned. Recently, a
newer approach of early, short-term, pre-treatment antifi-
brinolytic has been investigated (Table 3). In 1997, an
uncontrolled study found that a brief course of high-dose
EACA could result in a low rate of both rebleeding and DCI
[11]. EACA was administered to 307 patients with Hunt and
Hess grades I–III during the first 3 days following aneurys-
mal SAH. Therapy was started with a loading dose in the
emergency department or during transport, and early surgery
was performed when possible. Rebleeding occurred within
the first 48 h following aneurysm rupture in 1.3% of patients,
symptomatic vasospasm in 23%, and stroke in 8%. Since
2002, there have been three published reports: one ran-
domized trial of 505 patients (254 treated with TXA within
48 h) [3], and the two retrospective cohort controlled trials of
EACA administered within 72 h (356 treated in one trial [6]
Table 3 Antifibrinolytic therapy after aneurysmal SAH
Reference Study design
Hillman et al. [3] Randomized, prospective, multicenter
study of patients with SAH verified
within 48 h of first hospital admission
N = 254 TXA
N = 251 controls
Harrigan et al. [6] Retrospective review
N = 356
Starke et al. [16] Prospective, observational study
N = 73 treated with EACA
N = 175 controls
SAH subarachnoid hemorrhage
123
Neurocrit Care (2011) 15:241–246
and 73 in the other trial [16]) The randomized trial found
reductions in rebleeding from 10.8 to 2.4%, a 19% reduction
in poor outcome, and a 4% increase in good outcome [3].
While the functional outcomes were not statistically signif-
icant, rebleeding reductions were significant. There was no
difference in the incidence of DCI. In the first case–control
study, using contemporaneously untreated patients at the
same institution, incident rebleeding was reduced from 11.4
to 2.7%, with a 10% improvement in good outcomes [16].
When evaluating only good-grade patients, functional out-
comes as well as the differences in rebleeding were both
statistically significant. There was no difference in DCI or
pulmonary embolism, although incidence of deep venous
thrombosis was significantly increased. In the larger case–
control trial using only historical controls from the literature,
there also seemed to be a beneficial effect with rebleeding
occurring in 1.4% and DCI in 7.2% [6]. Of note, three of the
five rebleeds in this large cohort were in patients allocated to
treatment with antifibrinolytic therapy who never received a
dose because they bled before it could be given.
Method of Aneurysm Repair: Implications
for Rebleeding
A major determinant of rebleeding is whether the aneurysm
is completely excluded from the circulation via either
microsurgical or endovascular treatment. In ISAT, inci-
dence of early and long-term rebleeding was assessed in
patients receiving endovascular coiling versus microsurgi-
cal clipping [12–14]. While there was a small difference in
the early and late rebleeding rates, with surgical exclusion
resulting in less rebleeding, this difference was small and
the effect on overall outcome was minor. Some have crit-
icized these data as underestimating the beneficial effects
of microsurgical prevention of rebleeding on functional
Antifibrinolytic Incidence rebleeding,
antifibrinolytic
vs control
TXA at diagnosis and every 6 h until 2.4 vs. 10.8% (P < 0.01)
aneurysm occlusion or 72 h
Short-term EACA administered before 1.4%
aneurysm surgery, which occurred an
average of 47 h after admission
Short-term EACA before aneurysm 2.7 vs. 11.4% (P = 0.019)
treatment
Neurocrit Care (2011) 15:241–246
outcome. Marked delays (mean 0.6 days) in the performance
of clipping were linked to an expected increase in pre-
treatment rebleeds and these delays would be unusual in
typical clinical practice. Other limitations include the lack of
intraoperative or even postoperative angiography in the
microsurgical arm and high intraoperative rupture rate.
Despite the fairly low risk of long-term rebleeding in patients
undergoing endovascular treatment, each ensuing follow-up
study from the ISAT cohort makes it increasingly clear that
serial follow-up of coiled aneurysms in young patients is
critical and that the better repair expected from microsurgery
continues to prevent morbidity from re-bleeding, even years
later [15]. In contrast to clipping or coiling, there is very little
evidence that alternative treatments (e.g., glue or aneurysmal
wrapping) provide significant protection from rebleeding.
More recently, the investigations have assessed the use of
intracranial stents as an alternative treatment for patients that
cannot be treated with coiling or clipping along [46, 47].
There are currently limited long results from these alterna-
tive therapies, and they are generally recommended only as a
salvage technique after failed primary treatment or in
patients whose aneurysm morphology does not allow for
clipping or coiling.
Conclusions
Older studies suggest that rebleeding occurs in about 4% of
patients during the first 24 h following after initial aneu-
rysmal SAH, and 1–2% per day over the next 14 days.
These studies likely missed hyperacute rebleeding occur-
ring during the first 8 h after SAH. When very early
rebleeding is also considered, incidence of rebleeding is
likely to be close to 12% in the first 24 h. Rebleeding is
especially common in those patients in poor clinical con-
dition, those with large aneurysms, those presenting with
loss of consciousness or sentinel hemorrhage, and patients
exposed to very early (<3 h) angiographic workup. Early
repair of the aneurysm by either microsurgical clip ligation
or coil embolization is critical in limiting the morbidity
associated with rebleeding, but some delay is inevitable in
arranging these procedures as they are technically com-
plicated and most safely performed in high volume centers.
A short course of anti-fibrinolytic therapy has been shown
to reduce rebleeding and, if discontinued immediately after
early aneurysm repair, may actually improve outcome,
although data showing outcome are not yet conclusive.
References
1. Ameen AA, Illingworth R. Anti-fibrinolytic treatment in the pre-
operative management of subarachnoid haemorrhage caused by
245
ruptured intracranial aneurysm. J Neurol Neurosurg Psychiatry.
1981;44:220–6.
2. Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Koike T, Tanaka R.
Ultra-early rebleeding in spontaneous subarachnoid hemorrhage.
J Neurosurg. 1996;84:35–42.
3. Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Ja-
kobsson KE. Immediate administration of tranexamic acid and
reduced incidence of early rebleeding after aneurysmal sub-
arachnoid hemorrhage: a prospective randomized study.
J Neurosurg. 2002;97:771–8.
4. Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal sub-
arachnoid hemorrhage: outcomes for a consecutive series of 391
patients not selected by grade or age. J Neurosurg. 2002;97:
250–8.
5. Larsen CC, Eskesen V, Hauerberg J, Olesen C, Romner B, Astrup
J. Considerable delay in diagnosis and acute management of
subarachnoid haemorrhage. Dan Med Bull. 2010;57:A4139.
6. Harrigan MR, Rajneesh KF, Ardelt AA, Fisher WS 3rd. Short-
term antifibrinolytic therapy before early aneurysm treatment in
subarachnoid hemorrhage: effects on rehemorrhage, cerebral
ischemia, and hydrocephalus. Neurosurgery. 2010;67:935–9.
7. Jane JA, Winn HR, Richardson AE. The natural history of
intracranial aneurysms: rebleeding rates during the acute and long
term period and implication for surgical management. Clin
Neurosurg. 1977;24:176–84.
8. Kassell NF, Torner JC. Aneurysmal rebleeding: a preliminary
report from the Cooperative Aneurysm Study. Neurosurgery. 1983;
13:479–81.
9. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kon-
gable GL. The international cooperative study on the timing of
aneurysm surgery. Part 1. Overall management results. J Neuro-
surg. 1990;73:18–36.
10. Kassell NF, Torner JC, Jane JA, Haley EC Jr, Adams HP. The
international cooperative study on the timing of aneurysm sur-
gery. Part 2. Surgical results. J Neurosurg. 1990;73:37–47.
11. Leipzig TJ, Redelman K, Horner TG. Reducing the risk of reb-
leeding before early aneurysm surgery: a possible role for
antifibrinolytic therapy. J Neurosurg. 1997;86:220–5.
12. Molyneux A, Kerr R, Stratton I, et al. International subarachnoid
aneurysm trial (ISAT) of neurosurgical clipping versus endo-
vascular coiling in 2143 patients with ruptured intracranial
aneurysms: a randomised trial. Lancet. 2002;360:1267–74.
13. Molyneux AJ, Kerr RS, Birks J, et al. Risk of recurrent sub-
arachnoid haemorrhage, death, or dependence and standardised
mortality ratios after clipping or coiling of an intracranial aneu-
rysm in the International Subarachnoid Aneurysm Trial (ISAT):
long-term follow-up. Lancet Neurol. 2009;8:427–33.
14. Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid
aneurysm trial (ISAT) of neurosurgical clipping versus endo-
vascular coiling in 2143 patients with ruptured intracranial
aneurysms: a randomised comparison of effects on survival,
dependency, seizures, rebleeding, subgroups, and aneurysm
occlusion. Lancet. 2005;366:809–17.
15. Plowman RS, Clarke A, Clarke M, Byrne JV. Sixteen-year sin-
gle-surgeon experience with coil embolization for ruptured
intracranial aneurysms: recurrence rates and incidence of late
rebleeding. J Neurosurg. 2011;114:863–74.
16. Starke RM, Kim GH, Fernandez A, et al. Impact of a policy of early
antifibrinolytic therapy for the prevention of acute rebleeding
after aneurysmal subarachnoid hemorrhage. Stroke. 2008;39:
2617–21.
17. Cha KC, Kim JH, Kang HI, Moon BG, Lee SJ, Kim JS. Aneu-
rysmal rebleeding: factors associated with clinical outcome in the
rebleeding patients. J Korean Neurosurg Soc. 2010;47:119–23.
18. Tong Y, Gu J, Fan WJ, Yu JB, Pan JW, Wan S, Zhou YQ, Zheng
XJ, Zhan RY. Patients with supratentorial aneurysmal
123
246
subarachnoid hemorrhage during the intermediate period: waiting
or actively treating. Int J Neurosci. 2009;119:1494–506.
19. Ruigrok YM, Slooter AJ, Rinkel GJ, Wijmenga C, Rosendaal FR.
Genes influencing coagulation and the risk of aneurysmal sub-
arachnoid hemorrhage, and subsequent complications of
secondary cerebral ischemia and rebleeding. Acta Neurochir
(Wien). 2010;152:257–62.
20. Tanno Y, Homma M, Oinuma M, Kodama N, Ymamoto T.
Rebleeding from ruptured intracranial aneurysms in North East-
ern Province of Japan. A cooperative study. J Neurol Sci. 2007;
258:11–6.
21. Heelingman CA, van den Bergh WM, Beijer IS, et al. Risk of
rebleeding after treatment of acute hydrocephalus in patients with
aneurysmal subarachnoid hemorrhage. Stroke. 2007;38:96–9.
22. Machiel Pleizier C, Algra A, Velthuis BK, Rinkel GJ. Relation
between size of aneurysms and risk of rebleeding in patients with
subarachnoid haemorrhage. Acta Neurochir. 2006;148:1277–9.
23. Beck J, Raabe A, Szelenyi A, et al. Sentinel headache and the risk
of rebleeding after aneurysmal subarachnoid hemorrhage. Stroke.
2006;37:2733–7.
24. Kitsua Y, Suzuki N, Sugiyama M, Yamamoto I. Changes in level
of consciousness and association with hyperglycemia as tool for
predicting and preventing re-bleeding after spontaneous sub-
arachnoid hemorrhage. Prehosp Disaster Med. 2006;21:190–5.
25. Ruijs AC, Dirven CM, Algra A, Beijer I, Vandertop WP, Rinkel
G. The risk of rebleeding after external lumbar drainage in
patients with untreated ruptured cerebral aneurysms. Acta Neu-
rochir. 2005;147:1157–61.
26. Kusumi M, Yamada M, Kitahara T, et al. Rerupture of cerebral
aneurysms during angiography—a retrospective study of 13
patients with subarachnoid hemorrhage. Acta Neurochir. 2005;
147:831–7.
27. Naidech AM, Ianjua N, Kreiter KT, et al. Predictors and impact
of aneurysm rebleeding after subarachnoid hemorrhage. Arch
Neurol. 2005;62:410–6.
28. McIver JI, Friedman JA, Wijdicks EF, et al. Preoperative ven-
triculostomy and rebleeding after aneurysmal subarachnoid
hemorrhage. J Neurosurg. 2002;97:1042–4.
29. Edner G, Ronne-Engström E. Can early admission reduce aneu-
rysmal rebleeds? A prospective study on aneurysmal incidence,
aneurysmal rebleeds, admission and treatment delays in a defined
region. Br J Neurosurg. 1991;5:601–8.
30. Steiger HJ, Fritschi J, Seiler RW. Current pattern of in-hospital
aneurysmal rebleeds. Analysis of a series treated with individu-
ally timed surgery and intravenous nimodipine. Acta Neurochir.
1994;127:21–6.
31. Roos YM, Beenen LM, Goren RM, Albrecht KW, Vermeulen M.
Timing of surgery in patients with aneurysmal subarachnoid
haemorrhage: rebleeding is still the major cause of poor outcome
in neurosurgical units that aim at early surgery. J Neurol Neu-
rosurg Psychiatry. 1997;63:490–3.
123
Neurocrit Care (2011) 15:241–246
32. Hillman J, von Essen C, Leszniewski W, Johansson I. Signifi-
cance of ‘‘ultra-early’’ rebleeding in subarachnoid hemorrhage.
J Neurosurg. 1988;68:901–7.
33. Larsen CC, Eskesen V, Hauerberg J, Olesen C, Romner B, Astrup
J. Considerable delay in diagnosis and acute management of
subarachnoid haemorrhage. Ugeskr Laeger. 2010;172:1442.
34. Girvin JP. The use of antifibrinolytic agents in the preoperative
treatment of ruptured intracranial aneurysms. Trans Am Neurol
Assoc. 1973;98:150–2.
35. van Rossum J, Wintzen AR, Endtz LJ, Schoen JH, de Jonge H.
Effect of tranexamic acid on rebleeding after subarachnoid
hemorrhage: a double-blind controlled clinical trial. Ann Neurol.
1977;2:238–42.
36. Chandra B. Treatment of subarachnoid hemorrhage from rup-
tured intracranial aneurysm with tranexamic acid: a double-blind
clinical trial. Ann Neurol. 1978;3:502–4.
37. Maurice-Williams RS. Prolonged antifibrinolysis: an effective
non-surgical treatment for ruptured intracranial aneurysms? Br
Med J. 1978;1:945–7.
38. Kaste M, Ramsay M. Tranexamic acid in subarachnoid hemor-
rhage. A double-blind study. Stroke. 1979;10:519–22.
39. Fodstad H, Forssell A, Liliequist B, Schannong M. Antifibrinol-
ysis with tranexamic acid in aneurysmal subarachnoid
hemorrhage: a consecutive controlled clinical trial. Neurosurgery.
1981;8:158–65.
40. Vermeulen M, Lindsay KW, Murray GD, et al. Antifibrinolytic
treatment in subarachnoid hemorrhage. N Engl J Med. 1984;
311:432–7.
41. Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risks of
antifibrinolytic therapy in the management of ruptured intracra-
nial aneurysms. A double-blind placebo-controlled study. Acta
Neurochir. 1990;102:1–10.
42. Roos Y. Antifibrinolytic treatment in subarachnoid hemorrhage: a
randomized placebo-controlled trial. Star study group. Neurol-
ogy. 2000;54:77–82.
43. Jane JA, Kassell NF, Torner JC, Winn HR. The natural history of
aneurysms and arteriovenous malformations. J Neurosurg.
1985;62:321–3.
44. Kassell NF, Drake CG. Timing of aneurysm surgery. Neurosur-
gery. 1982;10:514–9.
45. Roos, Y.B., Rinkel, G., Vermeulen, M., Algra, A., van Gijn, J.:
Antifibrinolytic therapy for aneurysmal subarachnoid haemor-
rhage. Cochrane Database Syst Rev. 2003;CD001245.
46. Lylyk P, Miranda C, Ceratto R, et al. Curative endovascular
reconstruction of cerebral aneurysms with the pipeline emboli-
zation device: the Buenos Aires experience. Neurosurgery. 2009;
64:632–42.
47. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D.
The pipeline embolization device for the intracranial treatment of
aneurysms trial. Am J Neuroradiol. 2011;32:34–40.