Accepted Manuscript

Ultra-early treatment for poor-grade aneurysmal subarachnoid hemorrhage: a

systematic review and meta-analysis

Yangyun Han, MD, Feng Ye, MD, Xiaodong Long, MD, Aiguo Li, MD, Hong Xu, MD,
Linbo Zou, MD, Yumin Yang, MD; Chao You, MD

PII: S1878-8750(18)30712-5
DOI: 10.1016/j.wneu.2018.03.219
Reference: WNEU 7832

To appear in: World Neurosurgery

Received Date: 5 March 2018

Revised Date: 29 March 2018
Accepted Date: 30 March 2018

Please cite this article as: Han Y, Ye F, Long X, Li A, Xu H, Zou L, Yang Y, You M;C, Ultra-early
treatment for poor-grade aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis,
World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.03.219.

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 ACCEPTED MANUSCRIPT

Full title: Ultra-early treatment for poor-grade aneurysmal subarachnoid hemorrhage:

a systematic review and meta-analysis
Short title: Ultra-early treatment for poor-grade aSAH
Yangyun Han 1,2, #, MD; Feng Ye 2,#, MD; Xiaodong Long2, MD; Aiguo Li2, MD;
Hong Xu2, MD; Linbo Zou2, MD; Yumin Yang2, MD; Chao You1,*, MD

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1 Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu,
Sichuan, P. R.China.

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2 Department of Neurosurgery People’s Hospital of Deyang City Deyang Sichuan
P. R. China

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Yangyun Han: hans_lion@163.com; Feng Ye: fengye028@126.com; Xiaodong Long:
xiaodonglong0838@126.com; Aiguo Li: aiguoli0838@126.com; Hong Xu:

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hongxu0838@126.com; Linbo Zou: lbzou21@163.com; Yumin Yang:
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154429038@qq.com.
#These authors contributed equally to this work
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*Corresponding author:
Chao You
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Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu,

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Sichuan, P. R.China;
Tel: +86-028-85422972; Fax: +86-0838-2220098;
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Email: chaoyou_neuro@126.com.
Key words: aneurysmal subarachnoid hemorrhage, poor-grade, ultra-early treatment,
meta-analysis, systematic review
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 ACCEPTED MANUSCRIPT

Abstract
Objective
It remains unknown if ultra-early (within 24 hours after SAH onset) treatment could
improve prognosis in poor-grade aneurysmal subarachnoid hemorrhage (aSAH). We
aimed to evaluate the effect of ultra-early treatment on the functional outcome and

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mortality in poor-grade aSAH patients via systematic review and meta-analysis.
Methods: We performed a literature search in PubMed, MEDLINE and Web of

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Science databases. Primary outcomes were death and functional outcome assessed at
any time period. Secondary outcomes were rebleeding rate before aneurysm occlusion

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procedure and incidence of intraoperative technique difficulty (ITD). The results are
demonstrated as odds ratios (OR) with 95% confidence intervals (CI).

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Results: A total of 14 articles containing 1111 patients met the inclusion criteria. The
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pooled incidence was 47% (95% CI 40%–54%) for favorable outcome across 13
studies, 26% (95% CI 19%–32%) for mortality in 11 studies, 10% (95% CI 3%–16%)
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for rebleeding in 5 studies, and 20% (95% CI 10%–31%) for ITD in 5 studies after
ultra-early treatment of poor-grade aSAH. When compared with delayed treatment
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( 24h), the ultra-early treatment failed to improve the outcome (OR=1.23 [95% CI
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0.75 to 2.01]; p=0.40) or reduce the mortality(OR=0.84 [95% CI 0.58 to 1.22];

p=0.45), but tended to prevent preoperative rebleeding(OR=0.59 [95% CI 0.32 to
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1.07]; p=0.08) in 6, 4 and 4 case-control studies, respectively.

Conclusions: Current evidence showed no significant change both in functional
outcome and mortality between ultra-early and delayed treatment although ultra-early
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treatment may be associated with lower rebleeding rate.

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Introduction
Aneurysmal subarachnoid hemorrhage (aSAH) is a severe condition of hemorrhagic
stroke. According to the clinical severity, those with Hunt-Hess grade IV and V and
World federation of neurosurgical society (WFNS) grade IV and V are ascribed to
poor-grade aSAH8. Poor-grade aSAH accounts for approximately 18%-24% across all

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aSAH with more than 60% patients dead or disabled after treatment28. Many factors
are identified as significant predictors of unfavorable functional outcome after

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poor-grade aSAH, including age, WFNS grade V, signs of cerebral herniation,
aneurysm size, presence of space-occupying hematoma, and rebleeding in patients

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with poor-grade aSAH19.
Rebleeding is a severe consequence predictive of poor prognosis after aSAH24.

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Rebleeding is more common in the poor-grade than good-grade population associated
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with higher mortality rates and poorer functional outcome. It was noted that
rebleeding occurred in 20% poor-grade patients compared to 5% patients with good
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clinical condition, especially within the first 12 hours9. van den Berg et al. further
reported that only 1 patient recovered functionally among 26 rebleeding patients with
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WFNS grade V, suggesting that less than 5% patients could gain a favorable outcome
after rebleeding in poor-grade aSAH 26.
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Although poor-grade SAH patients may benefit from early aneurysm repair to
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prevent rebleeding and guidelines recommend aneurysm treatment as early as

logistically and technically possible to reduce the risk of rebleeding for all grades of
aSAH23,2, the optimal timing of treatment remains to be determined. Before 1990s,
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patients were often treated with delayed operation waiting for the remission of brain
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swelling. Currently, the treatment strategy tends to be earlier within 48-72h. Recently,
ultra-early surgery within 24 hours after SAH onset has been advocated to maximally
minimize the rebleeding and facilitate the early aggressive treatment of possible
vasospasm15. This strategy is not without criticism. One of the concerns is the
difficulty in operative control because of brain swelling and the risk of accelerating
brain injury in already edematous and hyperemic brain tissue9. Furthermore, some
authors advocated “wait and see” strategy to identify the subgroup with reversible
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brain function18, 29
. To be specific, patients are fully resuscitated with sedation,
ventilation and fluid supply for 24h. After that, patients were re-evaluated to observe
any neurological improvement. Only improved patients are undergoing further DSA
diagnosis and aneurysm occlusion. Under this policy, it was demonstrated that more
than half patients whose grade improved within 24h had a favorable outcome after

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aneurysm clipping in poor aSAH18.
We aimed to collect the available data and make a meta-analysis regarding the

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ultra-early timing in treating poor-grade aSAH to provide the strong evidence for the
clinical decision-making.

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Methods
Search strategy

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An electronic literature search of PubMed, MEDLINE (Ovid), and Web of Science
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(Thomson Reuters) (last update on 12-Jan-2018) was performed by two
investigators(Yangyun Han and Feng Ye). The free search terms and key words
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related to “aSAH”, “intracranial/cerebral aneurysm(s)”, “poor/high-grade”, “grade

IV/V”, “timing”, “ultra-early”, “24 hours” were used in combination. We also
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attempted to make contact with the authors of original studies to gain additional
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information. The research results were limited in English language without

restrictions on dates. This study was conducted according to the preferred reporting
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items for systematic reviews and meta-analysis (PRISMA) guidelines. Search strategy
was listed in Appendix.
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Inclusion criteria
We included studies that met the criteria as follows: (1) RCT, or prospective or
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retrospective studies addressing the participants with aSAH diagnosed by CT or

lumbar puncture. (2) Patients should be categorized as poor- grade aSAH (Hunt-Hess
or WFNS grade IV to V). (3) Treatment modality should at least contain aneurysm
clipping or coiling. (4) Treatment timing was clearly defined as hours or days after
symptom onset or as categorized variable such as ultra-early vs. early or late
management. Ultra-early timing should be less than 24 hours after symptom onset.
(5) Outcomes are evaluated by mRS or GOS, or extended GOS at any time period.
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Alternatively, studies categorizing outcome into good recovery, moderate disability,

severe disability and death were also included.
Exclusion criteria
Studies were excluded if patients were preoperatively in good condition (H-H or
WFNS grade I-III), if treatment was limited in external ventricular drainage or

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decompressive craniectomy alone, if the treatment timing was not clearly stated or
defined as less than 24h of admission rather than aSAH onset, or if the functional

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outcome was not reported. Studies of single case reports, pure review or animal
investigation were also excluded.

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Study eligibility
Two authors (Xiaodong Long, Aiguo Li) independently screened search records to

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decide which study should be included. If disagreement occurred, a senior author
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(Chao You) would make the final decision through discussion and consensus.
Data extraction
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For each study, the following information was extracted independently by two
investigators: study design, inclusion/exclusion criteria, study sample, age, gender,
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preoperative condition (WFNS grade), aneurysm characteristics (site, size),

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concomitant complications (hydrocephalus, intracerebral hematoma, subdural

hematoma), treatment modality (clipping, coiling), treatment timing, duration of
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follow-up and functional outcome. The primary outcomes were mortality and
favorable outcome which was defined as mRS ≤3 or GOS >3. The secondary outcome
was preoperative rebleeding rate and the incidence of intraoperative technique
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difficulty (ITD). ITD was defined if one of the following criteria was met: (1)
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Difficult access because of brain swelling noted by the surgeon; (2) Intraoperative
aneurysm rupture; (3) Temporary clip application lasting more than 5 minutes; (4)
Evidence of retraction injury (i.e., focal swelling, contusion) or early postoperative
infarction seen on computed tomographic scans; (5) New early postoperative
neurological deficit.
Quality assessment
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The methodological quality of the included studies was measured by two independent
investigators using the Newcastle–Ottawa Scale (NOS) for cohort studies.
Heterogeneity among studies was evaluated using Cochran’s χ2 test of homogeneity
(Q test) and I2 index. A threshold of p<0.05 was used to declare statistical significance
for heterogeneity. Random-effects models were used to combine crude ORs

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accounting for both within-study variance and between-study heterogeneity.
Publication bias was evaluated by the use of the Egger regression asymmetry test, and

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funnel plots were also generated using Stata software if the meta-analysis included
more than 9 studies according to the Cochrane Handbook.

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Statistical analysis
Pooled estimates and event rates with 95% CIs from all studies were combined using

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a random-effects model. Statistical comparisons were performed only for studies that
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contained matched control groups. For each outcome, odds ratios and 95% CIs were
calculated. The Z-test was used to determine the significance of pooled odds ratios.
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Furthermore, subgroup analysis was carried out to evaluate the impact of the
preoperative condition on the results. We considered p values of less than 0.05 to be
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significant. All statistical analyses were performed using Stata Software (version 13
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[Stata Corp., College Station, Texas, USA]). and a comprehensive meta-analysis

software suite (BioStat, Inc.).
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Results
Study selection
A total of possible 2383 articles were identified via PubMed, Medline and Web of
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Science database search. After removing duplicates and screening titles and abstracts,
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we performed full-text reviews of 26 articles. Further full-text examination led to the

exclusion of 12 articles, which left only 14 studies1, 4, 5, 9, 11, 13, 17, 20-22, 25, 27, 30, 33 eligible
for analysis. The processes and stages of inclusion and exclusion for papers were
showed in the PRISMA flow diagram (Figure 1).
Study characterization
Detailed clinical information from the eligible studies with or without matched
control group was described in Table 1 and Table 2, respectively. There were 3
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prospective and 11 retrospective studies. The years of publications ranged from 1998
to 2017. The sample size of patients was widely variable ranging from 9 to 258. For 7
studies lacking control group, the average age of patients was around 50 years and
male proportion ranged from 0.1 to 0.67; grade IV accounted for the most cases in 5
studies and only one exclusively included patients of Grade V; the vast majority

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aneurysms were located in the anterior circulation and secured via clipping. For most
studies with matched control group, the demographic data and radiographic

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parameters were not available (Table 2). Three case-control studies described the
detailed clinical severity and treatment modality (Table 3). In two studies, the clinical

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condition was much severe in ultra-early treatment group with more patients having
Grade V aneurysm, intracerebral hematoma and brain herniation. However, in the

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study by Tykocki25, patients in ultra-early group were significantly younger. All
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studies except one described the period of follow up which was “discharge” in 3, 3
months in 1 and 6 months or longer in 9 studies. The NOS score of eligible studies
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ranged from 6 to 9.
Results of individual studies and synthesis of results
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Overall effect of ultra-early surgery on functional outcomes and mortality

Of the 14 eligible studies, 13 studies1, 4, 5, 9, 11, 13, 17, 20-22, 25, 27, 33 containing 806 patients
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recorded the favorable functional outcome. Pooled analysis showed overall incidence
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of favorable functional outcome was 47% (95% CI 40%-54%)(Figure 2).

Random-effect model was used as the degree of heterogeneity was significant (p <
0.001, chi-square–based Q test; I2 test > 70%). When stratified by follow-up period,
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we found that the rate of good functional outcome was higher in 6 months or longer
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time than that of 3 months or discharge(50% [95% CI 40%-60%] vs 42% [95% CI

33%-51%])(Figure 3A) . When stratified by the treatment modality(Figure 3B), the
incidence was 38% [95% CI 33%-44%]) in studies1, 4, 9, 13, 20, 33 where all patients were
managed by aneurysm clipping, 61% [95% CI 49%-74%]) in studies11, 21, 27 where all
patients were managed by aneurysm coiling, and 52% [95%CI 38%-65%]) in studies5,
17, 22, 25
where patients were managed by either aneurysm clipping or coiling.
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Sensitivity analysis showed that the results were not heavily influenced by specific
studies.
Eleven studies1, 4, 5, 9, 13, 20-22, 25, 27, 33 involving a total of 696 patients described the
mortality. Tests of heterogeneity revealed that I2 was 68.9% with P<0.001, indicating
moderate heterogeneity. Random effects model revealed a mortality of 26% (95% CI

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19%-32%)(Figure 4A). Sensitivity analysis showed that the results were heavily
influenced by the study9 by Laidlaw and Siu where up to 45% mortality was reported.

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After removing this study (very small sample size), the overall mortality was 23% (95%
CI 19%-26%) (Figure 4B). When stratified by follow up time in the remaining 10

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studies (Figure 5A), the mortality was (23% [95% CI 18%-29%]) in 6 months or
longer follow-up studies1, 4, 5, 21, 27, 33, and (20% [95% CI 15%-25%]) in studies of 3

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months/discharge follow up13, 22, 25. When stratified by treatment modality (Figure
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5B), the mortality was 29% [95% CI 23%-36%]) in studies1, 4, 13, 20, 33
where all
patients were managed by aneurysm clipping, 18% [95% CI 4%-32%]) in studies21, 27
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where all patients were managed by aneurysm coiling, and 20% [95% CI 16%-25%])
in studies5, 22, 25 where patients were managed by either aneurysm clipping or coiling.
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Overall effect of ultra-early surgery on preoperative rebleeding rate and the

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occurrence of ITD
Data on the occurrence of preoperative aneurysm bleeding were available in 5
studies11, 25, 27, 30, 33 involving 184 patients. The pooled incidence was 10% (95% CI
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3%-16%) (Figure 6A). The sensitivity analysis showed that the results were heavily
influenced by the study33 by Zhao et al. where the incidence is lower to 2%. After
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removing this study, the pooled incidence of rebleeding was 13% (95% CI 8%-17%).
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Four studies5, 9, 13, 21 reported the occurrence of ITD in 278 patients with major
heterogeneity (I2= 72.2%, P = 0.013) (Figure 6B). In the excluded study27 by van
Loon where patients were solely treated by coiling, no technical complications
directly related to the endovascular procedure occurred. More specifically, no cerebral
thromboembolism, no occlusion of parent vessels, and no perforation of the aneurysm
wall during coiling were noted. However, in one study of very small sample13, ITD
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was encountered in 5 out of 9 (55.6%) patients treated by aneurysm clipping. Overall,

the pooled incidence of ITD was 20% (95% CI 10%-31%).
Patients who underwent ultra-early surgery versus matched controls
Six case-control studies1, 11, 17, 22, 25, 33 reported the incidence of favorable functional
outcome in 636 patients. The likelihood of a favorable outcome was not significantly

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different among patients who underwent ultra-early surgical treatment relative from
that of the matched controls (OR 1.23 [95% CI 0.75–2.02]; p = 0.40) (Figure 7).

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However, remarkable heterogeneity was observed (I2= 73.5%, P = 0.002). The
following sensitivity analysis demonstrated that the results were heavily affected by

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the study33 by Zhao et al. where the clinical condition was significantly much severe
in the ultra-early treatment group than in the delayed group (larger ICH, higher

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proportion of grade V and more frequent brain herniation). When omitting this study,
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the heterogeneity is equivocal (I2= 58%, P = 0.049); the incidence of a favorable
outcome was significantly higher in ultra-early treatment group in fixed model (OR
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1.37 [95% CI 1.07–1.76]; p = 0.013) (Figure 8A), and tended to be higher in random
effects model (OR 1.48 [95% CI 0.94–2.35]; p = 0.092) (Figure 8B).
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Four case-control studies1, 22, 25, 33

reported the incidence of mortality in 468
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patients. The likelihood of mortality was not significantly different among patients
who underwent ultra-early surgical treatment relative from that of the matched
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controls (OR 0.84 [95% CI 0.58–1.22]; p = 0.446) (Figure 9A). No heterogeneity was
observed (I2= 24.9%, P = 0.262).
Four case-control studies11, 25, 30, 33 reported the incidence of rebleeding rate in
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333 patients. The incidence of rebleeding tended to be lower in patients who

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underwent ultra-early surgical treatment (OR 0.59 [95% CI 0.32–1.07]; p = 0.084)

(Figure 9B). No heterogeneity was observed (I2= 0.0%, P = 0.965).
Assessment of publication bias
No asymmetry was seen in the funnel plots for either pooled favorable
outcome(Figure 10A) or mortality analysis(Figure 10B). Statistical measures of
publication bias determined by the Egger scores were not significant for the
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meta-analysis of favorable outcome (p=0.362), mortality (p=0.488) and rebleeding

rate (p=0.119).
Discussion
This is the first meta-analysis concentrating on the effect of ultra-early treatment in
patients with poor-grade aSAH. The results suggest that the prognosis of poor-grade

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aSAH patients are not always dismal as prior reports described. Actually, our overall
pooled analysis showed that nearly half patients receiving ultra-early treatment could

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recover functionally and less than one third would die. Although no statistically
significant functional improvement was observed in poor-grade aSAH patients under

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ultra-early treatment in the meta-analysis of eligible case-control studies, there is a
trend towards favorable outcome. This may be partially realized by preventing fatal

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aneurysm rebleeding as a great tendency of reduced rebleeding rate was also
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identified in the present study.
Ultra-early treatment and outcomes
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Patients presenting with poor-grade aSAH have commonly been reported to have a
poor prognosis. de Oliveira et al3 reported a single-center cohort combined with a
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systematic review of studies recording functional outcome in the poor-grade aSAH

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population. The mortality rate was 60% and the overall favorable outcome was gained
in 28% patients. When the studies were grouped into decades, favorable outcome
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increased from 13% in the late 1970s to early 1980s to 35% in the late 1980s to early
1990s, and remained unchanged thereafter. However, our results showed the pooled
incidence was 47% (95% CI 40%–54%) for favorable outcome across 13 studies, 26%
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(95% CI 19%–32%) for mortality in 11 studies after ultra-early aggressive treatment.

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The improved outcome may be due to the reduced rebleeding which is more common
in poor- than good-grade aSAH. Other advantages include early intracranial pressure
(ICP) control and perfusion pressure improvement by evacuating accompanied
parenchymal hematoma and/or cerebrospinal fluid drainage, and starting early “3H”
therapy to prevent vasospasm.
Our meta-analysis failed to demonstrate significant improvement of functional
outcome in patients undergoing ultra-early treatment when compared with those
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accepting treatment more than 24 hours after aSAH. However, after excluding the
study with significant baseline bias, there is a tendency of improved outcome. The
results are consistent with that reported by other studies including all grades of aSAH.
Oudshoorn et al12 performed a meta-analysis of previous 4 studies comparing
functional outcomes in patients treated <24 and >24 h after aSAH in 902 patients,

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finding that treatment (clipping or coiling) <24 h was associated with less poor
functional outcome (OR=0.76 [95 % CI 0.61–0.94]). Rawal et al16 also found that

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treatment <1 day was associated with a reduced odds of poor outcome compared with
treatment >1 day (OR=0.40 [95% CI 0.28 to 0.56]) by sole endovascular treatment in

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aSAH. Zhao et al. defined ultra-early timing as within 48h of aSAH and found that
ultra-early treatment is associated with improved clinical outcomes in poor-grade

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aSAH in their meta-analysis32. The insignificant results in the present meta-analysis
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may be explained as followed. First and foremost, the baseline imbalance is presented
in most eligible studies as mentioned before. Ultra-early treatment group usually had
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more critical patients with brain herniation, Grade V of aSAH and intracerebral
hemorrhage25, 33. The fact that patients with brain herniation more often undergo
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ultra-early surgery may produce selection bias. Besides, the definition of favorable
outcome varied. Two of the studies11, 17 defined as mRS
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2 rather than as broadly

accepted as mRS 3, which means that a part of patients with mRS=3 have been
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asymmetrically distributed as unfavorable. Third, there are higher surgical risk in

poor-grade than low-grade aSAH and the benefit of ultra-early treatment may be
offset by the disadvantages. The relatively high incidence of intraoperative technique
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difficulty suggests that additional iatrogenic brain injury may relate to unfavorable
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outcome. Forth, delayed treatment was defined with a wide range as more than 24
hours. No further specific timings such as 24-72h (early therapy) or 3d can be
sub-classified because of limited data. It has been reported that no outcome difference
was identified between treatment < 24h and treatment 24-72h12. The major concern of
ultra-early aneurysm treatment is the potential of increased periprocedural risks in
cases performed at night without the benefit of an optimal surgical or endovascular
team and with the potential for surgeon/staff fatigue34.
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Ultra-early treatment and rebleeding

The main potential benefit of ultra-early treatment in aSAH is to prevent aneurysm
rebleeding which is regarded as the single modifiable factor predicting poor
functional outcomes6. However, the preventability of rebleeding by ultra-early
aneurysm occlusion is controversial. Park et al14 investigated the effect of a

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24-hour-a-day formal emergency treatment protocol (median times from aSAH to
aneurysm occlusion < 8 hours) in patients with a ruptured aneurysm on the incidence

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of rebleeding and clinical outcomes, observing significant reduction of rebleeding (2.1%
vs 7.4%) and improvement of functional outcome(87.9% vs 79.7%) compared with a

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broadly defined early treatment (< 3 days). However, a recent study found that
implementation of a 24-hour ultra-early aneurysm repair protocol would only result in

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a 0.3% reduction in the incidence of rebleeding because most rebleeding occurred
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prior to admission to the hospital10. Our study found that the occurrence of rebleeding
tended to be lower in patients undergoing ultra-early treatment although no statistical
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significance was achieved (p=0.084). This conclusion is perfectly consistent with the
time intervals from aSAH to rebleed that almost all rebleeds occur within 24 h and 83%
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within 12h with a median time interval of 3h between initial hemorrhage and rebleed 7,
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indicating that 24h treatment is not really early enough, and time period within 12h
may be more effective to dramatically prevent rebleeding. However, the less time
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interval means the greater challenge of logistics and staff preparation.

Limitations
There are several limitations in this systematic review and meta-analysis. First, only
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observational studies were eligible without a randomized controlled trial. The

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inherent selection bias is always possible. Second, patient age and clinical grade
(grade IV or grade V) are important factors affecting management strategy and the
timing of treatment. Those with older age or grade V tended to be treated in less
invasive modality and in later time. Attempts to subgroup analysis are not possible
because the detailed information could not be extracted separately. Third, there was
huge heterogeneity in most analyses. Although random-effects models were
performed, pertinent confounders including various outcome evaluating scales and
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differences in follow-up times across studies may contribute to the heterogeneity.

Although subgroup analysis was performed in the raw pooled analysis showing that
endovascular coiling is superior to clipping, the selection bias is remarkable for
patients with elevated ICP due to intracerebral hemorrhage or subdural hemorrhage
are usually excluded from coiling treatment. In contrast, a recent meta-analysis

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demonstrated that the outcome with coiling is not superior to clipping in patients with
poor-grade aSAH and coiling has a surprisingly greater risk of mortality31. In the

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present meta-analysis, no any conclusion in terms of treatment modality can be
suggested due to the lack of pertinent information in the eligible studies.

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Conclusions
Poor-grade aSAH remains a therapeutic challenge. With ultra-early aneurysm coiling

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or clipping, approximately half patients can recover favorably and less than one third
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patients will die. Compared to delayed treatment, no significant benefits were
observed by ultra-early treatment although there is a tendency of reduced rebleeding
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rate. These results should be interpreted with caution for high-level studies are lacking.
More evidence from large prospective cohorts is needed.
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Figure 1. Flow diagram showing the processes of study selection

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Figure 2. Forest plot of studies focusing on the favorable outcome of all the patients.
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Figure 3. Forest plot of studies focusing on the favorable outcome of patients
stratified by follow-up period (3A) or by treatment modality (3B).
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Figure 4. Forest plot of studies focusing on mortality of all the patients (4A) or after
excluding one study which heavily influenced the result (4B).
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Figure 5. Forest plot of studies focusing on the mortality of patients stratified by

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follow-up period (5A) or by treatment modality (5B).

Figure 6. Forest plot of studies focusing on the rebleeding (6A) or intraoperative
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technique difficulty (6B) of all the patients.

Figure 7. Forest plot of studies focusing on the favorable outcome of patients with
matched control group.
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Figure 8. Forest plot of studies focusing on the favorable outcome of patients with
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matched control group after excluding one study which heavily influenced the result.
Meta-analysis in fixed model (8A), meta-analysis in random model (8B).
Figure 9. Forest plot of studies focusing on the mortality (9A) and rebleeding (9B) of
patients with matched control group.
Figure 10. Funnel plot of studies evaluating the incidence of the favorable outcome
(10A)and mortality (10B).
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Table 1. Studies without a control group for patients undergoing ultra-early operation with poor-grade aSAH
Study Design No. Age Male G-IV Site Size ICH Clip Follow-up Favorable Mortality Pre-op ITD

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( %) (%) (ACA) (mm) (%) (%) outcome rebleed
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Duke, 1998 R 27 56.5 0.30 1.0 0.70 11 ND 100 0.48 0.33 ND ND
Shimoda, R 74 57 ND 0.57 0.96† ND 0†† 100 ND 0.42 0.3 ND ND

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van Loon, P 10 49.4 0.1 0 0.90 12 0 0 18m 0.6 0.2 0.18 0

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2002

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Laidlaw, P 132 ND ND ND ND ND ND 100 3m 0.40 0.45 ND 0.14
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Shin, 2005 R 18 52.2 0.67 0.78 0.61 10.6* 0 0 13.7m 0.67 0.17 ND 0.11

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Eleftherios R 109 ND** 0.45 0.56 0.90 ND 0.26 85 6m 0.56 0.21 ND 0.25

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Pan, 2009 R 9 47.6 0.44 0.67 1.0 8 ND 100 discharge 0.44 0.22 ND 0.56

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†, in 5 cases the aneurysm site was unknown; ††, ICH of all patients <10ml; *, 4 patients were missing ; **, age ranging from11 to 70.
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No. , number of patients; m, months; G-IV, Grade IV; ACA, anterior circulation aneurysm; ICH, intracerebral hematoma;

pre-op, preoperative; ITD, intraoperative technical difficulty; R, retrospective; P, prospective; ND, not described.
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Table 2. Studies with a matched control group for patients undergoing ultra-early operation with poor-grade aSAH
Study Country Design Followup No. of Favorable outcome Mortality Rebleed

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patients n(%) n(%) n(%)
U/D Ultra-early Delayed Ultra-early Delayed Ultra-early Delayed

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Shiraos( 2010) Japan Retrospective discharge 219/39 78(35.6) 14(35.9) 49(22.4) 8(20.5)
Wong(2011) China Prospective 6m 60/36 7(11.7) 8(22.2)

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Sandström Australia Retrospective 6m 80/42 47(58.8) 22(52.4)
(2013)

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Luo(2015) China Retrospective 6m 31/14 18(58.1) 3(21.4) 5(16.1) 3(21.4)

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Zhao(2015) China Retrospective 12.5m 45/68 14(31.3) 39(57.4) 15(31.9) 22(31.0) 1(2.2) 2(2.9)
Chen(2016) China Retrospective 6m 15/3 4(26.7) 0(0) 3(20.0) 1(33.3)

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Tykocki(2017) Poland Retrospective discharge 38/41 22(57.9) 9(22.0) 5(13.2) 14(34.1) 4(10.5) 8(19.5)
m, months; U, ultra-early; D, delayed;

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Table 3. Case-controlled studies with detailed clinical data in patients undergoing ultra-early operation with poor-grade aSAH
Factor Luo 2015 Zhao 2015 Tykocki 2017

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Ultra-early Delayed Ultra-early Delayed Ultra-early Delayed
Sample size 31 14 47 71 38 41

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Mean age (year) 62.6 55.6 53.9 55.5 49.5 65.8*
Male n(%) 13(41.9) 6(42.9) 21(44.7) 29(40.8) 18(47) 16(39)

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Grade IV n(%) 28(90.3) 13(92.9) 19(40) 52(73)* 27(71) 22(54)
ICH n(%) 0(100) 0(100) 30(64) 28(40)* 24(63) 8(20)*

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Brain herniation n(%) ND ND 23(49) 11(16)* 22(58) 6(15)*&

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ACA n(%) 27(87.1) 14(100) 47(100) 68(95.8) 33(87) 34(83)
Size (mm) 5.6 6.8 6.0 6.3 ND ND

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Clip n(%) 0(0) 0(0) 47(100) 71(100) ND ND
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ICH, intracerebral hematoma; ACA, anterior circulation aneurysm; ND, not described.

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1. This is the first meta-analysis investigating the effect of ultra-early (within 24h
after aSAH onset) aneurysm occlusion treatment on the functional outcome and
mortality in poor-grade aSAH;
2. The influence of ultra-early treatment on rebleeding and intraoperative technique
difficulty was also analyzed;

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3. Currently, this is the best evidence regarding the role of ultra-early treatment timing
in poor-grade aSAH.

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aSAH: Aneurysmal subarachnoid hemorrhage;

CI: confidence intervals;

CT: computerized tomography;

DSA: Digital subtraction angiography

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GOS : Glasgow Outcome Scale;

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H-H: Hunt-Hess;

ITD: intraoperative technique difficulty;

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mRS: modified Rankin Scale;

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NOS: Newcastle–Ottawa Scale
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OR: odds ratios;

RCT: randomized controlled trial;

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WFNS: World federation of neurosurgical society

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