Neurocrit Care (2022) 36:1071–1079

https://doi.org/10.1007/s12028-022-01493-4

REVIEW ARTICLE

A Comparison Between Enteral

and Intravenous Nimodipine in Subarachnoid
Hemorrhage: A Systematic Review and Network
Meta-Analysis
Federico Geraldini1* , Alessandro De Cassai1, Paolo Diana1, Christelle Correale1, Annalisa Boscolo1,
Stefano Zampirollo2, Laura Disarò2, Anna Carere2, Nicola Cacco2, Paolo Navalesi1,2 and Marina Munari1

© 2022 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Abstract
Our objective was to compare the effectiveness of intravenous and enteral nimodipine in preventing poor outcome
from delayed cerebral ischemia in patients with subarachnoid hemorrhage. We performed a systematic search and a
network meta-analysis using the following databases: PubMed, Scopus, the Cochrane Central Register of Controlled
Trials, and Google Scholar. Risk of Bias 2 tool was used to assess risk of bias of included studies. A ranking among
methods was performed on the basis of the frequentist analog of the surface under the cumulative ranking curve.
Published studies that met the following population, intervention, comparison, outcomes and study (PICOS) criteria
were included: patients with subarachnoid hemorrhage aged 15 years or older (P); nimodipine, intravenous and oral
formulation (I); placebo or no intervention (C); poor outcome measured at 3 months (defined as death, vegetative
state, or severe disability), case fatality at 3 months, delayed cerebral ischemia, delayed ischaemic neurologic deficit,
and vasospasm measured with transcranial Doppler or digital subtraction angiography (O); and randomized con-
trolled trials (S). No language or publication date restrictions were applied. Ten studies were finally included, with a
total of 1527 randomly assigned patients. Oral and intravenous nimodipine were both effective in preventing poor
outcome, delayed cerebral ischemia, and delayed ischaemic neurological deficit. Neither treatment was effective in
improving case fatality. Evolving clinical protocols over a 30-year period and the risk of bias of the included studies
may limit the strength of our results. Enteral and intravenous nimodipine may have a similar effectiveness in terms of
preventing poor outcome, delayed cerebral ischemia, and delayed ischaemic neurological deficit. More research may
be needed to fully establish the role of intravenous nimodipine in current clinical practice.
Keywords: Subarachnoid hemorrhage, Nimodipine

Introduction smaller studies and directly compared against enteral

Enteral nimodipine is widely used and recommended
by current guidelines for the treatment of patients with
subarachnoid hemorrhage (SAH) [1–3]. Comparatively,
intravenous nimodipine has been analyzed by fewer,
*Correspondence: federico.geraldini@aopd.veneto.it
1
Institute of Anaesthesia and Intensive Care, Padua University Hospital,
Via Giustiniani 1, Padua 35127, Italy
Full list of author information is available at the end of the article
nimodipine in only three studies [4–6]. According to
current evidence, intravenous nimodipine is only rec-
ommended as an alternative for patients who cannot
receive the enteral formulation as a “good clinical prac-
tice,” as seen in the most recent Guidelines for Subarach-
noid Hemorrhage published by the Korean Society of
Cerebrovascular Surgeons in 2018 [3]. However, some
authors advocate that enteral bioavailability may be lower
1072
than expected in certain subsets of patients, with neg-
ligible serum concentrations reported in patients with
high-grade SAH, therefore suggesting that in some cases
parenteral administration may be superior [7]. Conclu-
sive evidence on the benefit of intravenous nimodipine
compared with the enteral route in SAH is not currently
available. The aim of this network meta-analysis was to
evaluate if different routes of nimodipine administra-
tion can influence outcome at 3 months in patients with
SAH. Secondary objectives were to evaluate case fatal-
ity at 3  months, incidence of delayed cerebral ischemia
(DCI), delayed ischaemic neurological deficit (DIND),
and vasospasm incidence.
Methods
This article was prepared following the Preferred Report-
ing Items for Systematic reviews and Meta-Analysis
(PRISMA) Statement Guidelines [8]. The PRISMA
checklist is available as supplemental content (SC) 1.
The protocol of this systematic review and meta-
analysis was written and registered in PROSPERO
(CRD42021254447).
Eligibility Criteria
Published studies that met the following population,
intervention, comparison, outcomes and study (PICOS)
criteria were included: patients with SAH aged 15  years
or older (P); nimodipine, intravenous, and oral formula-
tion (I); placebo or no intervention (C); poor outcome
measured at 3 months (defined as death, vegetative state,
or severe disability), case fatality at 3 months, incidence
of DCI, DIND, and vasospasm (O); and randomized con-
trolled trials (RCTs) (S).
Exclusion criteria were the following: (1) simple
descriptive literature (reviews); (2) prospective and retro-
spective observational studies; (3) literature without ran-
domized controls; (4) studies with randomized grouping
after cerebral vasospasm occurred; (5) RCTs without at
least one of the following endpoints: outcome, case fatal-
ity, DCI, DIND; and (6) nonpeer reviewed articles.
Search Strategy
We performed a systematic search of the medical lit-
erature for the identification, screening and inclusion
of articles. The search was performed in the following
databases (last updated May 11th, 2021): PubMed, Sco-
pus, the Cochrane Central Register of Controlled Trials,
and Google Scholar. We also checked the reference lists
of included studies and of any related search results. For
specific information regarding our search strategy, see SC
2. We did not apply any restriction on the language or the
year of publication.
Study Selection
Two researchers (AC and LD) independently screened
titles and abstracts of the identified articles in order
to select relevant and irrelevant articles. Each citation
was reviewed in full-text form if considered potentially
relevant.
Data Extraction and Data Retrieval
After identifying those studies meeting the inclusion
criteria, two authors (CC and SZ) manually reviewed
and assessed each of the included studies. Any disa-
greement on both study selection and data extraction
was resolved through consultation with a fourth author
(PD).
The following information was collected for each arti-
cle: first author, year of publication, total number of
patients per group, form of intervention (enteral or intra-
venous nimodipine), type of control (placebo, enteral,
or intravenous nimodipine), reported result for patients
with poor outcome (severe disability, vegetative state,
or death), overall mortality, DCI, DIND, and vasospasm
incidence.
If data were missing and contact details were avail-
able, a request for further information was sent by email
to the corresponding author of the study. If no reply was
received after our initial request, a second message was
sent 7  days later, followed by a third and final request
1 week after the second one.
Quality Assessment and Certainty of Evidence Assessment
Two researchers (NC and A.D.C.) independently evalu-
ated the quality of included RCTs by using the Risk of
Bias 2 tool [9]. Disagreements were resolved by discus-
sion with a third researcher (AB).
An overall risk of bias was expressed on a three-grade
scale (“low risk of bias,” “high risk of bias,” or “some
concerns”).
We used the Grades of Recommendation, Assess-
ment, Development and Evaluation (GRADE) approach
to assess the certainty of evidence related to each of the
outcomes [10].
Statistical Methods
Data meta-analysis was performed using statistical soft-
ware R version 4.1 (R Foundation for Statistical Comput-
ing, Vienna, Austria) with the package “netmeta.”
Treatment effect for dichotomous outcomes was
expressed as odds ratio (OR) with 95% confidence

interval (CI). A ranking among methods was per-
formed on the basis of the frequentist analog of the
surface under the cumulative ranking curve [11]. Zero
events were treated by applying a continuity correction
adding one to each value.
Inconsistency, Heterogeneity, and Publication Bias Analysis
For the assessment of study heterogeneity, the χ2
test and I2 statistic were used (considering I2 values
as the following: low < 25%, moderate 25–50%, and
high > 50%) [12]. Within design heterogeneity and
between design inconsistency was evaluated using the
Cochrane Q test. Publication bias was evaluated both
by a visual inspection of funnel plots (SC 6) and by the
Fig. 1 Flowchart of the study. RCT, randomized controlled trial
1073
Egger test for any outcome with ten or more studies (p
value < 0.05 as an index of a possible publication bias).
Results
Study Selection and Data Retrieval
Search results are shown in the PRISMA diagram (Fig. 1).
The initial search found 2602 articles, the assessment for
duplicates excluded 915 of these items, and the remain-
ing 1687 articles were screened. Search results with
nonsuitable details in the title or abstract were subse-
quently excluded and 100 full-text articles were retrieved.
Among these, 14 articles were found to be RCTs involv-
ing intravenous or enteral nimodipine. After additional
review, four studies were excluded (reasons leading to the
exclusion are presented in SC 5), and a total of ten stud-
ies evaluating patients receiving intravenous and enteral

Table 1 Characteristics of included studies
Author (year) Comparators
Allen (1983) [18] Enteral nimodipine (C1)
and placebo (C2)
Philippon (1986) [17] Enteral nimodipine (C1)
and placebo (C2)
Messeter (1987) [19] Intravenous nimodipine
(C1) and placebo (C2)
Neil-Dwyer (1987) [15] Enteral nimodipine (C1)
and placebo (C2)
Petruk (1988) [14] Enteral nimodipine (C1)
and placebo (C2)
Ohman (1988) [16] Intravenous nimodipine
(C1) and placebo (C2)
Pickard (1989) [13] Enteral nimodipine (C1)
and placebo (C2)
Kronvall (2009) [5] Intravenous nimodipine
(C1), enteral nimodipine
(C2)
Liu (2010) [6] Intravenous nimodipine
(C1), enteral nimodipine
(C2)
Soppi (2012) [4] Intravenous nimodipine
(C1), enteral nimodipine
(C2)
C1, comparator 1, C2, comparator 2, DCI, delayed cerebral ischemia, DIND, delayed ischaemic neurologic deficit, GOS, Glasgow Outcome Scale, SAH, subarachnoid hemorrhage
1074
Patients (C1, C2) Country Clinical grade Nimodipine dose Duration of treatment Outcome indicators
58, 63 USA and Canada Hunt and Hess I–II 3 mg/kg divided in six 21 days DIND, death, severity of
daily doses neurological deficit after
21 days of treatment
39, 42 France Hunt and Hess I–III 360 mg/d 21 days DIND, death, GOS at 21 day
after SAH
13, 7, 0 Sweden Hunt and Hess I–III 48 mg/d > 9 days DIND, death, functional
outcome without time
indication
38, 37 United Kingdom Hunt and Hess I–V 360 mg/d 21 days Death, DIND, good or poor
functional outcome at
3 months
91, 97 Canada Hunt and Hess III–V 540 mg/d 21 days Evaluation of GOS on day
21 days and 3 months
after SAH. DCI, DIND, case
fatality
104, 109 Finland Hunt and Hess I–III 0.5 μg/kg/min 7–10 days, then converted Outcome at 3 months,
to enteral nimodipine death, DCI, DIND
until day 21
278, 276 United Kingdom World Federation of 360 mg/d 21 days DCI, death, GOS at 3 months
Neurosurgeons I–V
57, 49 Sweden Hunt and Hess I–V 48 mg/d > 10 days (continued Incidence of DINDs, DCI,
if signs of vasospasm clinical outcome based
or delayed ischaemic on the GOS at 3 months,
neurologic deficit) death
36, 32 China Hunt and Hess I–V 24 mg/d intravenous 21 days Death and neurologic out-
nimodipine, 90 mg/d come at 21 days, DIND
enteral nimodipine
87, 84 Finland Hunt and Hess I–V 48 mg/d 10 days, then switched to Incidence of DIND, DCI,
enteral nimodipine until clinical outcomes at 3
day 16 and 12 months after SAH,
death

formulation of nimodipine were finally included in the
analysis (Table 1). With respect to missing data, only two
of the corresponding authors replied: one was unable to
provide further information [5], whereas the other pro-
vided data for outcome at 3 months [4].
Study Characteristics
The ten included studies randomly assigned a total of
1527 patients. Among these, 601 were allocated to a con-
trol group receiving placebo or no intervention, whereas
926 received nimodipine (289 intravenous nimodipine,
637 enteral nimodipine).
According to the risk of bias evaluation, four studies
were at high risk of bias while some concerns arose for
the remaining six (Fig.  2). The motivations guiding the
assignment of the risk of bias judgments are available as
supplementary material (SC 3).
Outcomes
The overall network analysis is summarized in Table  2
and graphically depicted in Fig.  3 and Fig.  4. Further-
more, specific direct, and indirect evidence is available as
supplementary material (SC 4).
Poor Outcome
Poor outcome (death, vegetative state, or severe dis-
ability) at 3  months was evaluated in six studies [4, 5,
Fig. 2 Bias assessment. Overview of the ROB2 assessment
1075
13–16]. Both treatment modalities with enteral and with
intravenous nimodipine were effective in preventing
poor outcome, with an OR for intravenous nimodipine
of 0.60 (95% CI 0.38–0.98) compared with 0.58 (95% CI
0.42–0.78) for enteral nimodipine. Enteral nimodipine
ranked higher with a slightly superior P-score (P-score
of 0.681 for intravenous nimodipine and 0.809 for enteral
nimodipine).
Overall certainty of evidence assessed with GRADE is
rated as low because of the random allocation not being
concealed and the wide confidence intervals, albeit with
low heterogeneity (I2 0%).
Case Fatality
Excluding the four studies reporting outcome before
3  months, neither treatment was effective in reducing
case fatality compared with the placebo (Table 2).
Overall certainty of evidence assessed with GRADE is
rated as low because of moderate heterogeneity (I2 35.2%)
and random allocation not being concealed.
DCI
Five studies evaluated DCI [4, 5, 13, 14, 16]. Treatment
with intravenous and enteral nimodipine were equally
effective in preventing DCI, both with an OR of 0.57:
intravenous nimodipine OR 0.57 (95% CI 0.37–0.90),
enteral nimodipine OR 0.57 (95% CI 0.42–0.79). Enteral
1076

Table 2 Results of the network meta-analysis and the corresponding rank

Parameter Enteral nimodipine Intravenous nimodipine Placebo

Patients (N = 1527) 637 289 601

Poor outcome
OR (95% CI) 0.58 (0.42–0.78) 0.60 (0.38–0.98) –
p value < 0.001* 0.040* –
Rank (P-score) 1 ( 0.809) 2 (0.681) –
Case fatality
OR (95% CI) 0.77(0.47–1.28) 0.80 (0.39–1.62) –
p value 0.328 0.536 –
Rank (P-score) 2 (0.685) 1 (0.599) –
DCI
OR (95% CI) 0.57 (0.42–0.79) 0.57 (0.37–0.90) –
p value < 0.001* 0.014* –
Rank (P-score) 1 (0.751) 2 (0.746) –
DIND
OR (95% CI) 0.43(0.28–0.65) 0.38 (0.23–0.62) –
p value < 0.001* < 0.001* –
Rank (P-score) 2 (0.647) 1 (0.853) –
CI, confidence interval, DCI, delayed cerebral ischemia, DIND, delayed ischaemic neurologic deficit, OR, odds ratio
*
Statistically significant values

nimodipine was ranked higher with a marginally supe-

rior P-score (P-score of 0.751 for enteral nimodipine and
0.746 for intravenous nimodipine).
Overall certainty of evidence assessed with GRADE is
rated as moderate because of the random allocation not
being concealed, albeit with low heterogeneity (I2 0%).

Delayed Ischaemic Neurologic Deficit

Nine studies evaluated DIND [4–6, 14–19] and both
treatments were effective in reducing its incidence, with
an OR of 0.43 (95% CI 0.28–0.65) for enteral nimodipine
and 0.38 (95% CI 0.23–0.62) for intravenous nimodipine.
Intravenous nimodipine ranked higher with a P-score of
0.867 compared with 0.633 for enteral nimodipine.
Fig. 3 Network graph. Overview of the network

Fig. 4 Forest plots of the network meta-analysis. CI, confidence interval, OR, odds ratio

Overall certainty of evidence assessed with GRADE is
rated as moderate because of the random allocation not
being concealed, albeit with low heterogeneity (I2 0%).
Discussion
The main result of this meta-analysis suggests that
enteral and intravenous nimodipine may be equally effec-
tive for patients with SAH. In particular, the summary of
direct and indirect evidence available shows that enteral
and intravenous nimodipine are both effective in reduc-
ing the incidence of poor outcome, DCI, and DIND,
whereas both are ineffective in reducing SAH related
mortality. Although enteral nimodipine has been used
for over 30 years for the prevention of vasospasm-related
complications, current evidence on the use of intrave-
nous nimodipine in the prevention of vasospasm is not
conclusive, and the current guidelines only recommend
it as “good clinical practice” for specific patients [1–3].
Limited evidence has been collected regarding the use of
intravenous nimodipine for the prevention of vasospasm-
related complications against placebo [16, 19–23], and
the two formulations have been directly compared only
in a few relatively small trials, which reported no differ-
ence in outcome and no relative benefit for intravenous
nimodipine [4–6].
This network meta-analysis was conducted in order to
assess whether intravenous nimodipine in patients with
SAH could be an effective alternative to enteral nimodi-
pine in current clinical practice. Recent literature has
cast doubts on the exclusive use of enteral nimodipine,
suggesting it may not be adequate for all patients. For
instance, in patients unable to swallow, the administra-
tion of nimodipine through the nasogastric tube has
been associated with reduced or negligible serum con-
centrations. This issue seems to occur more frequently
in patients with “high-grade SAH” and, in this specific
context, intravenous administration could be considered
a reasonable alternative to the enteral formulation [7].
Furthermore, recent evidence reports that intravenous
nimodipine may be associated with higher serum and
spinal fluid concentrations [24]. On the other hand, intra-
venous nimodipine has been associated with a greater
incidence of hypotension, requiring more dose adjust-
ments to maintain mean arterial pressure [25].
In our analysis, the use of enteral nimodipine was
slightly superior in terms of incidence of poor outcome
and DCI, but was slightly less effective when considering
DIND. However, given the large CI overlap as shown in
Fig.  3, neither treatment appears to be clearly superior
to the other. From this analysis we can summarize that
both treatments appear to be effective and the selected
formulation may be chosen primarily on the basis of
patient-related factors (e.g., evaluation of absorption
1077
for the enteral route, availability of adequate intrave-
nous access for the parenteral route, patient toleration of
selected route) rather than always recurring to one or the
other. Of note, enteral administration of nimodipine was
very consistent among the different studies, which uni-
versally used a treatment duration of 21 days [13–15, 17,
18]. On the other hand, only one study evaluated the use
of intravenous nimodipine for the full 21 days of therapy
[6], with most studies initiating the acute treatment with
intravenous nimodipine subsequently converted to the
enteral formulation after 7–10 days [4, 16] or suspended
treatment after 9–10  days if there was no evidence of
vasospasm [5, 19]. However, given the relatively small
size of the involved studies, no analysis was performed
to compare different intravenous regimens. Further-
more, a comparison of the two routes of administrations
with respect to their adverse effects and the incidence of
vasospasm measured angiographically or with transcra-
nial Doppler was not possible because the available data
were deemed insufficient and too diverse to elaborate an
analysis.
Previous meta-analyses confirmed the usefulness of
enteral nimodipine on poor outcome and of intravenous
nimodipine on DCI and DIND, but could not make rec-
ommendations regarding the benefit of the intravenous
route with respect to outcome [26, 27]. Three recent
network meta-analyses have been published on the
treatment of patients with SAH, however none of these
analyses compared nimodipine considering the enteral
and intravenous formulation. The conclusions regarding
the best agents to use after SAH differed between the var-
ious studies. In particular, the study by Yu et al. [28] con-
cludes that nimodipine and cilostazol are effective after
SAH, whereas Dayyani et al. [29] found that nimodipine,
nimodipine with magnesium and high-dose clazosentan
could potentially be effective in preventing morbidity
and mortality in patients with SAH [29]. Lastly, Mishra
et  al. [30] concluded that nicardipine prolonged-release
implants and cilostazol could improve outcome after
SAH.
In our study, which compares intravenous and enteral
nimodipine, the inclusion of three additional studies
performing a direct comparison of the two formulations
allowed us to conduct a network meta-analysis. Adding
these direct confrontations to the existing body of evi-
dence coming from placebo controlled trials, we found
that also the intravenous route may potentially prevent
poor outcomes. The results of this study suggest that
a reevaluation of the role of intravenous nimodipine is
warranted in current practice, considering also that this
formulation is currently available in Europe but not in the
USA. Although our results perhaps do not provide suf-
ficient certainty of evidence to universally recommend
1078
its use and do not permit an evaluation of which sub-
set of patients could benefit more from one formulation
or the other, they do strongly suggest that intravenous
nimodipine could be a viable alternative to its enteral
counterpart and that its future use should be given care-
ful consideration. More high-quality RCTs are necessary
to properly evaluate this aspect. Future investigations
should aim to confirm the positive effect on outcome,
analyze the differences in effectiveness in patients with
different SAH severity and compare the adverse effects of
the two formulations.
This study presents some limitations that we would like
to discuss. First, no studies were evaluated with a low
risk of bias, with six studies showing some concerns and
four studies showing high risk of bias. Second, treatment
duration and dose for intravenous nimodipine, though
similar among studies, was less standardized than its
enteral counterpart. Third, we restricted our research to
four databases and we cannot exclude that other studies
could have been identified by exploring different data-
bases. Fourth, the included studies were published over
a 30-year period and evolving clinical protocols and out-
come definitions may limit the reliability of the derived
findings. Fifth, this result represents an average result
among patients with different characteristics and clinical
presentations. Further studies may be needed to properly
define the use of intravenous nimodipine in the context
of precision medicine. Furthermore, most included arti-
cles did not present supplementary analyses assessing the
efficacy of nimodipine in patients with different clinical
or radiological presentations and we were therefore una-
ble to stratify our results by SAH severity.
Conclusions
Our study shows that intravenous and enteral nimodipine
may be equally effective in patients with SAH in terms of
preventing poor outcome, DCI, and ischaemic neurologi-
cal deficits. However, more high-quality RCTs are needed
to evaluate potential differences in effectiveness in terms
of outcome and if certain subsets of patients could ben-
efit more from one or the other formulation.
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1007/s12028-022-01493-4.
Author details
1 2018;61(2):127–66.
Institute of Anaesthesia and Intensive Care, Padua University Hospital, Via
Giustiniani 1, Padua 35127, Italy. 2 Department of Medicine (DIMED), Univer-
sity of Padua, Via Vincenzo Gallucci 13, Padua 35121, Italy.
Acknowledgements
We would like to thank Dr. Timo Koivisto and Dr. Aku Kaipainen for providing
valuable additional data for our research. We would like to thank Dr. Tommaso
Pettenuzzo for his precious input in perfecting our article and for reviewing
the statistical analysis.
Author Contributions
F.G.: conceived the idea with A.D.C., registered the trial on PROSPERO,
contacted corresponding authors for missing data, helped with the statistical
analysis, and wrote and edited the article. A.D.C.: conceived the idea with F.G.,
performed the statistical analysis, performed Risk of Bias 2 (ROB2) evalua-
tion, and revised and edited the article. P.D.: supervised the screening phase
and resolved disputes involving included studies, screened for duplicates,
and helped with the writing of the article. C.C.: Performed the initial search,
reviewed full-text articles for potential inclusion, helped with data extraction,
and revised and edited the article. A.B.: resolved disputes with ROB2 assess-
ment, performed Grades of Recommendation, Assessment, Development and
Evaluation assessment, supervised data extraction, and revised and edited
the article. S.Z.: reviewed full-text articles for potential inclusion, helped with
data extraction, and revised and edited the article. L.D.: performed the initial
screening of abstracts, retrieved the full-text articles of included articles, and
revised and edited the article. A.C.: performed the initial screening of abstracts,
retrieved full-text articles of included articles, and revised and edited the
article. N.C.: performed an additional check on the initial screening phase to
evaluate articles, retrieved and analyzed previous systematic reviews poten-
tially of interest, helped with ROB2 evaluation, and helped edit the article.
P.N.: supervised the project, helped with the interpretation and contextualiza-
tion in current literature of the results, and assessed and edited the finalized
article. M.M.: helped conceive and plan the idea, assessed it for overall merit,
supervised the project, helped with the interpretation and contextualization
in current literature of the results, and assessed and edited the finalized article.
All authors discussed the results and approved the final manuscript.
Source of Support
None.
Conflict of interest
All authors declare that they have no conflict of interest.
Ethical Approval/Informed Consent
Because this was a systematic review and network meta-analysis, ethical
approval by our insitutional review board was not required.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 27 September 2021 Accepted: 14 March 2022
Published: 13 April 2022
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