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2. Original article
Intra-arterial nimodipine for cerebral vasospasm
after subarachnoid haemorrhage: Influence on
clinical course and predictors of clinical outcome
Asma Bashir1
, Morten Andresen1
, Jiri Bartek Jr1,2
, Marie Cortsen3
,
Vagn Eskesen1
and Aase Wagner3
Abstract
Intra-arterial nimodipine (IAN) has shown a promising effect on cerebral vasospasm (CV) after aneurysmal subarachnoid
haemorrhage. At our institution, Rigshospitalet, IAN treatment has been used since 2009, but the short- and long-term
clinical efficacy of IAN has not yet been assessed. The purpose was to evaluate the efficacy and clinical outcome of IAN
treatment of symptomatic CV, and to assess the predictors of clinical outcome. Medical records of 25 patients undergoing a
total of 41 IAN treatment sessions were retrospectively reviewed. Data on angiographic results, blood-flow velocities and the
clinical condition before and after the IAN treatment were recorded. Predictors of the clinical outcome were assessed with a
linear regression model. Positive angiographic response was achieved in 95.1% of 41 IAN treatment sessions. Flow-velocity
measurements showed no relationship with angiographic responses of IAN. The immediate clinical improvement was
observed in three patients (12%). Five patients (20%) had a favourable outcome at discharge and at three-month
follow-up; 10 patients (40%) had a moderate to poor outcome; and the rest (40%) died. Increased number of affected
vessels and number of procedures carried out per patient, and a trend toward an increased delay time from symptomatic CV
to confirming angiographic CV and thus instituting IAN treatment predicted the poor clinical outcome. IAN treatment
appears to be effective in reversing angiographic CV. However, it is not always effective in reversing clinical deterioration,
as several other factors including treatment delay affect the clinical course.
Keywords
Subarachnoid haemorrhage, cerebral vasospasm, intra-arterial nimodipine
Introduction
Cerebral vasospasm (CV) is a feared and potentially life-
threatening complication in patients following aneurys-
mal subarachnoid haemorrhage (SAH). Angiographic
CV is observed in up to 70% of patients, typically
between 4–14 days after the initial bleeding, and leads
to symptomatic brain ischaemia and/or new infarction
on radiographic imaging in about 30% of these
patients.1,2
Treatment of CV and prevention of delayed
cerebral ischaemia (DCI) is therefore a main goal in the
management of patients surviving from SAH. However,
despite maximal contemporary therapy and neurocritical
care, about 30% of these patients die, another 30% sur-
vive with significant disability, and the rest of them
recover with little or no long-term disability.3
Current medical strategies for prevention and
treatment of CV including endovascular therapies
with vasodilators and triple-H (i.e. hypertension, hyper-
volaemia, haemodilution) are suboptimal,2,4–8
as the
exact mechanisms leading to CV are not yet fully
elucidated.2,9
At the moment, nimodipine, a calcium
channel blocker, remains the only drug proved by the
US Food and Drug Administration, which is recom-
mended as the first-line treatment and prevention of
CV and improvement of outcomes after SAH.10,11
Although nimodipine exhibits neuroprotective as well
as vasodilatory benefits,2
some patients deteriorate fur-
ther and develop severe symptomatic CV. In the last
decade, a number of clinical trials have investigated
nimodipine infused directly in the spastic arteries
(intra-arterial nimodipine (IAN)), and found it to be
1
Department of Neurosurgery, Rigshospitalet, Faculty of Health and Medical
Sciences, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen,
Denmark
2
Department of Clinical Neuroscience, Section for Neurosurgery, Karolinska
Institutet and Department of Neurosurgery, Karolinska University Hospital,
Stockholm, Sweden
3
Department of Radiology, Rigshospitalet, Faculty of Health and Medical
Sciences, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen,
Denmark
Corresponding author:
Asma Bashir, Department of Neurosurgery, Rigshospitalet, Faculty of Health
and Medical Sciences, University of Copenhagen, Blegdamsvej 9, 2100
Copenhagen, Denmark.
Email: ab@asmabashir.com
The Neuroradiology Journal
2016, Vol. 29(1) 72–81
! The Author(s) 2016
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1971400915626429
neu.sagepub.com

3. effective in reversing angiographic CV, although overall
clinical outcome differs through the literature.12–18
At
our institution, Rigshospitalet, IAN treatment has been
used as the method of choice since 2009 whenever endo-
vascular treatment of CV was indicated. However, the
short- and long-term clinical efficacy of IAN has not yet
been assessed.
The purpose of this study was to retrospectively
evaluate the efficacy and clinical outcome of IAN treat-
ment of symptomatic CV, which is refractory to the
haemodynamic treatment, and to assess the predictors
of the clinical outcome.
Materials and methods
Data collection
Between December 2009–May 2012, 325 adults with
evidence of SAH on computerized tomography (CT)
scan were admitted to the neurosurgical intensive care
unit (ICU) at the University Hospital, Rigshospitalet,
in Copenhagen, Denmark. Only patients presenting
with a ruptured intracranial aneurysm on CT angio-
gram (CTA), suffering from symptomatic CV refrac-
tory to the haemodynamic therapy, and receiving
IAN treatment were reviewed. Twenty-eight patients
were identified. Among them, three patients were trea-
ted with a combination of percutaneous transluminal
angioplasty (PTA) and IAN, and were excluded to
avoid confound bias on clinical outcome, as PTA has
also shown to have beneficial effect.19
A total of 25
patients met the inclusion criteria and constituted the
study population. Data on these patients was extracted
from a computerized database and reviewed retrospect-
ively including demographic data, clinical condition at
admission based on World Federation of Neurological
Surgeons (WFNS) grade I–V,20
amount and distribu-
tion of subarachnoid blood detected by admission CT
by using the modified Fisher scale 1–4,21
and aneurysm
location as well as aneurysm treatment. Onset, location
and severity of CV, number of affected vessels, proced-
ure specifics such as dosage of IAN per vessel and per
procedure, and number of repeated procedures were
recorded. To assess the efficacy of IAN treatment,
the clinical response within 24 h (e.g. level of conscious-
ness based on Glasgow Coma Scale (GCS) and neuro-
logical condition), the angiographic response as well as
effects on blood flow-velocity of the middle cerebral
artery (MCA) determined by transcranial Doppler
(TCD) ultrasonography were examined. The clinical
outcome was assessed using the modified Rankin
scale (mRS) score at discharge and at three-month
follow-up.22
Informed consent was obtained from
patients or legal representative for patients with
impaired consciousness at the time of their clinical
work-up. The Board of Health Committee and Data
inspectorate approved the study. All the necessary pre-
cautions were taken to protect the identities of the
patients in the study.
Patient management and monitoring
All patients underwent either surgical or endovascular
obliteration of the ruptured aneurysm within 48 h after
the initial bleeding except seven patients who were hos-
pitalized 3–14 days after onset of SAH. Nimodipine
was administrated, orally or intravenously, in a dose
of 60 mg every 4 h in 21 days according to a standar-
dized SAH-protocol. Maintenance of euvolaemia was
achieved by administration of intravenous isotonic
crystalloid. When flow-velocity of the MCA exceeded
120 cm/s (a TCD cut-off value), triple-H therapy was
initiated for inducing prophylactic hypervolaemia
and elevating the mean arterial pressure by 20%.
Flow-velocity measurements were performed at least
once daily to monitor possible vasospastic activity.
Flow-velocity <120 cm/s was defined as normal,
120–150 cm/s as mild, 150–200 cm/s as moderate and
>200 cm/s as severe. Lindegaard ratio was not measured
routinely in all patients, and is therefore not mentioned
further in the study. The clinical condition was assessed
by continuous neurological examinations including GCS
scores.
Diagnosis of CV and IAN treatment
Cerebral vasospasm was suspected, if patients demon-
strated at least one of the following: (a) a decreased
level of consciousness and/or disorientation with a
decrease of at least two points on the GCS score from
baseline, (b) new focal neurological deficits (cranial
nerve palsy, hemiparesis and/or speech disturbances),
and/or (c) flow-velocity >120 cm/s. Neurological deteri-
oration was the main trigger for suspicion of CV, fol-
lowed by an increase in flow-velocity; the last was
mainly applied to patients with ventilator support.
Possible causes of neurological deterioration such as
presence of ischaemia, re-bleeding or hydrocephalus
on CT scan, electrolyte disturbance, seizures or hypoxia
were eliminated prior to CTA, which was usually per-
formed within 24 h of onset of symptomatic CV.
Degree of angiographic CV was assessed on a digital
subtraction angiography semi-quantitatively and
subjectively and classified as ‘none/mild’ when arterial
narrowing was <25% of the arterial diameter, ‘moder-
ate’ when narrowing was 25–50%, or ‘severe’ when
narrowing >50%.
Patients were found eligible for IAN treatment only
if they showed angiographic CV in territories
compatible with their neurological deficits and/or with
elevated mean flow-velocity. After dilution with 0.9%
saline to obtain a solution of 0.01 mg/ml, nimodipine
was administrated as an infusion over 20–40 minutes
through a microcatheter placed in the affected vessel.
Post-nimodipine angiograms were performed
10–30 min after each session. Two neuroradiologists
evaluated the angiographic results separately, and dis-
agreement was resolved by consensus. Each vessel was
evaluated as ‘responsive’ or ‘non-responsive’, and the
Bashir et al. 73

4. overall angiographic result was graded as ‘good
response’, ‘no response’ or ‘mixed response’. If persist-
ence or recurrence of CV was suspected, a new CTA
was performed, and IAN treatment was repeated after
the verification of angiographic CV and progressive
neurological deterioration.
Clinical evaluation
Immediate clinical response and flow-velocity measure-
ments within 24h after IAN treatment were recorded.
The change in the clinical condition was graded as
‘improved’, ‘unchanged’ or ‘worsened’. The clinical out-
come at discharge from the hospital and at three-month
follow-up was assessed using the mRS score (no question-
naire).22
A score 2 was considered as a good outcome.
Statistical analysis
Data analysis was performed with the statistical soft-
ware package IBM SPSS version 20.0. Descriptive data
was presented as median values with interquartile range
(IQR) in parentheses, as data was not normally
distributed. A p-value of less than 0.05 was accepted
as statistically significant. Our primary dependent vari-
able was mRS score, which was investigated in a linear
regression model based on following predictor
variables: age, WFNS grade, Fisher scale, aneurysm
location, severity of CV, number of affected vessels,
angiographic response and number of repeated proced-
ures. Significance of time delay in diagnosis of angio-
graphic CV and thus instituting IAN treatment was
assessed as well.
Results
Clinical assessment
Demographic data, WFNS grade, Fisher scale, and
location of aneurysm are presented in Table 1.
Surgical clipping was performed in seven (28%)
patients and endovascular occlusion was performed in
18 (72%) patients. All patients developed neurological
deterioration such as decreased level of consciousness,
hemiparesis, aphasia or other new focal neurological
signs between 4–13 days after onset of SAH (median,
eight days; IQR 6–9 days). Among them, two (8%)
patients already had neurological deficits at the time
of aneurysm treatment and one (4%) due to carotid
artery dissection two days prior to symptomatic CV.
One (4%) patient (no. 17) was admitted to the hospital
14 days after the initial bleeding and already had
developed left-sided arm paresis and leg paralysis due
to CV. In one (4%) patient (no. 15), who was artificially
ventilated, the suspicion of CV was raised by elevated
flow-velocity measurements only, which was the main
indication for angiography. The neurological deterior-
ation did not respond to the haemodynamic treatment.
Onset of occurrence of CV and neurological
deterioration including flow-velocity measurements
are summarized in Table 2.
Angiography and IAN treatment
Diagnostic cerebral angiography was performed within
24 h after onset of symptomatic CV in all patients
except nine (36%), in whom it was performed later
due to their fluctuating neurological condition. The
median time delay from the occurrence of symptomatic
CV to CTA was 14.5 h (IQR, 2.9–38.1 h). In most cases,
angiographic CV diffusely involved all vessels on both
sides of the circulation, while in six cases (24%) only
one side was affected involving 1–3 vessels. Overall, the
degree of CV was severe in 16 (64%) patients and mod-
erate in nine (36%). No one had a mild degree of CV.
In addition, seven (28%) patients showed signs of
incipient hypodensities on their CT scans. Using a
linear regression model with a significance p ¼ 0.048;
adjusted R2
¼ 0.241, severity of CV was significant asso-
ciated with an increased number of affected vessels
(p ¼ 0.004), but not with age (p ¼ 0.50), Fisher scale
(p ¼ 0.85) and aneurysm treatment (p ¼ 0.54). Severity
Table 1. Patient characteristics.
Demographic data
Age, median (years) 52
Female sex, no. (%) 20 (80%)
Risk factors, no. (%)
Hypertension 13 (52%)
Smoking 14 (56%)
Alcohol abuse 3 (12%)
Drug abuse 1 (4%)
WFNS grade I–V, no. (%)
I, II and III 15 (60%)
IV and V 10 (40%)
Fisher grade 1–4, no. (%)
1 and 2 3 (12%)
3 and 4 22 (88%)
Location of aneurysm, no. (%)
ACoA 9 (36%)
ACA 2 (8%)
MCA 4 (16%)
ICA 4 (16%)
PCA 1 (4%)
BA 4 (16%)
PICA 1 (4%)
Surgical or endovascular obliteration, no. (%)
Coils 14 (56%)
Clips 7 (28%)
Stent 3 (12%)
Coils/stent 1 (4%)
ACA: anterior cerebral artery; ACoA: anterior communicating artery; BA:
basilar artery; CV: cerebral vasospasm; ICA: internal cerebral artery; MCA:
middle cerebral artery; PCA: posterior cerebral artery; PICA: posterior infer-
ior cerebral artery; WFNS: World Federation of Neurological Surgeons.
74 The Neuroradiology Journal 29(1)

5. Table2.Theseverityofcerebralvasospasm(CV)andlocation,neurologicaldeficitincludingflowvelocity(FV),angiographicandclinicalresponsestotheintra-arterialnimodipine(IAN)treatmentand
clinicaloutcomeatdischargeandatthree-monthfollow-up(FU).
Patient/
sessionno.
Onsetof
sCV(day)
Neurological
deficits
Location
ofaCV
Severity
ofaCV
IANdoseper
session(mg)
Angiographic
response
Clinical
response
mRSscoresat
Discharge3-monthFU
1.110Lhemiparesis,5dayslaterRhemiparesis,FV70cm/sLMCA,ACA,ICASevere3.0GoodWorsened
1.2þAphasia,FV178cm/sLMCA,ACA,ICASevere3.0GoodUnchanged
1.3Sedated,FV190cm/sLMCA,ACA,ICASevere3.0MixedresponseUnchanged54
2.19FluctuatingDLC,Larmparesis,FV182cm/sMCAs,ACAs,ICAsSevere4.0GoodWorsened
2.2þSeizures,FV260cm/sACAs,MCASevere4.0GoodWorsened43
3.111FluctuatingDLC,FV187cm/sRMCAModerate3.2NoresponseUnchanged10
4.17Rhemiparesis,facialnervepalsy,visualaxisdeviation,FV
100cm/s
LACA,MCAModerate4.0GoodUnchanged54
5.19FluctuatingDLC,Llegparesis,FV193cm/sPCTSevere4.0GoodWorsened6–
6.15FluctuatingDLC,aphasia,FV180cm/sLMCA,ACAs,ICAsSevere4.0GoodWorsened6–
7.111FluctuatingDLCLMCA,MCAs,ICAs,PCTSevere4.0MixedresponseUnchanged
7.2þFV97cm/sRACA,MCA,ICASevere2.0GoodUnchanged53
8.16FluctuatingDLCaphasia,FV348cm/sACAs,MCAs,ICAs,PCTSevere4.0GoodWorsened
8.2SedatedACAs,MCAs,ICAs,PCTSevere6.0GoodWorsened56
9.15DLC,Lhemiparesisfacialnervepalsy,aphasia,FV
235cm/s
ACAs,MCAs,ICAsSevere6.0GoodWorsened
9.2SedatedACAs,MCAs,ICAsSevere6.0GoodUnchanged53
10.15DLC,Rhemiparesis,aphasiaACAs,MCAs,ICAsSevere4.8GoodUnchanged
10.2DLC,Rhemiparesis,aphasiaACAs,MCAs,ICAsSevere5.0MixedresponseUnchanged51
11.17FluctuatingDLC,Rhemiparesis,aphasiaPCTModerate4.0GoodUnchanged
11.2þVisialaxisdeviationPCTSevere4.0GoodUnchanged43
12.110DLC,FV156cm/sRACA,MCAs,ICAsSevere3.0GoodUnchanged6–
13.111DLC,Rhemiparesis,FV190cm/sACA,MCAs,ICAModerate4.4GoodUnchanged
13.2DLC,RhemiparesisACAs,MCAs,ICAsModerate5.0GoodWorsened6–
14.1a
6DLC,Rhemiparesis,facialnervepalsy,aphasia,FV
230cm/s
ACAs,MCAs,ICAsSevere4.0GoodWorsened6–
15.19Sedated,FV230cm/sACAs,MCAs,ICAsSevere5.0MixedresponseWorsened6–
16.19FluctuatingDLC,FV183cm/sACAsModerate4.5MixedresponseUnchanged32
17.113Lhemiparesis/paralysisACAs,MCAs,ICAsSevere4.0GoodWorsened
17.2þAphasia,FV250cm/sRACA,MCA,ICA,PCTSevere4.0GoodWorsened6–
18.18DLC,aphasia,FV145cm/sACAs,MCAs,ICAsSevere5.0GoodUnchanged
18.2þFV313cm/sLMCA,ICA,ACAsSevere4.0GoodUnchanged
18.3Sedated,FV257cm/sACAs,MCAs,ICAsSevere5.0GoodUnchanged
18.4Sedated,FV290cm/sLACA,MCA,ICASevere4.0MixedresponseUnchanged55
(continued)
Bashir et al. 75

6. of CV and number of affected vessels including ana-
tomic distribution are presented in Table 2.
Forty-one IAN treatment sessions were performed
in 25 patients (range, 1-4 treatment sessions per
patient), in which 173 vessels were evaluated. The
median time delay from angiographic CV to IAN treat-
ment was 3.0 h (IQR, 2–9.5 h). Median dose of nimodi-
pine was 4 mg per session (range, 2–6 mg per session),
while the largest single dose per vessel was 4 mg
(median, 2 mg; range, 1–4 mg). Complete reversal of
CV was successfully achieved in 31 (75.6%) treatments
(Figure 1); partial reversal was noted in eight (19.5%)
(Figure 2), while two (4.9%) showed no effect. There was
no significant correlation between the degree of CV and
angiographic response to IAN (p ¼ 0.24). Worsening of
CV did not occur during the procedures. No signs
of haemodynamic instability due to IAN infusion or
other procedure-related complications were observed.
However, in one (4%) patient (no. 14), a dosage of
2 mg nimodipine was accidently injected in a few seconds
causing transient drop in blood pressure. Dose per pro-
cedure, number of repeated procedures and angio-
graphic effects are summarized in Table 2.
TCD measurements
Complete results for flow-velocity measurements before
and after IAN treatment within 24h were available for
review in only 13 (32%) of 41 procedures. Mean velocities
decreased by 37cm/s in eight (20%) procedures,
unchanged in one (2%), and increased by 34cm/s in four
(10%). There was no correlation between flow-velocity
measurements and angiographic responses to IAN.
Clinical evaluation within 24 h after treatment, at
discharge and at three-month follow-up
The clinical condition remained unchanged for 12
(48%) patients, although all of them but one showed
angiographic response to IAN treatment. Three (12%)
patients showed clinical improvement based on GCS
scores and/or neurologically, two of them with none
and mixed responses to IAN. Ten (40%) patients
experienced a worsening in their clinical conditions
both consciously and neurologically; among them, six
(24%) had developed new neurological deficits. Two
(8%) had seizures at the time of wake-up call. Three
(12%) patients never regained consciousness and died a
few days later; all three had showed angiographic
response to IAN, two of them with mixed response.
In 12 (48%) patients, new cerebral infarctions were
observed on CT scan hours to a few days after the
IAN treatment.
At discharge, only one (4%) patient showed a good
clinical outcome (mRS 1). Two (8%) patients had a
moderate outcome (mRS 3) and 13 (52%) a poor out-
come (mRS 4–5). Nine (36%) patients died during hos-
pitalization, eight (32%) of them as a consequence of
extensive cerebral infarction secondary to CV (mRS 6).
Table2.Continued
Patient/
sessionno.
Onsetof
sCV(day)
Neurological
deficits
Location
ofaCV
Severity
ofaCV
IANdoseper
session(mg)
Angiographic
response
Clinical
response
mRSscoresat
Discharge3-monthFU
19.18DLC,aphasia,FV226cm/sLMCAModerate4.0NoresponseImproved32
20.15Pronation/extensionpattern,FV110cm/sRACA,MCA,ICAModerate3.0GoodWorsened
20.2þRhemiparalysis,Larmparesis,FV130cm/sRACA,MCA,ICASevere3.0GoodUnchanged53
21.19DLC,FV180cm7sACAs,ICAsSevere4.0GoodImproved42
22.16DLC,aphasiaLACA,ICA,MCAsModerate4.0GoodUnchanged54
23.16DLCLACA,MCAs,ICAsSevere4.0MixedresponseImproved53
24.14DLCACAs,MCAs,ICAs,PCTSevere6.0GoodUnchanged
24.2þRhemiparesis,FV200cm/sACAs,MCAs,ICAs,PCTSevere6.0GoodWorsened6–
25.16DLC,FV197cm/sLICA,ACAs,MCAs,PCTModerate6.0MixedresponseWorsened
25.2þRhemiparesis,extensorplantarreflex,FV237cm/sLACA,MCA,ICA,PCTModerate6.0GoodWorsened6–
ACA:anteriorcerebralartery;aCV:angiographiccerebralvasospasm;DLC:decreasedlevelofconsciousness;FU:follow-up;IAN:intra-arterialnimodipine;ICA:internalcerebralartery;L:leftcirculation;MCA:middlecerebral
artery;PCT:posteriorcirculatoryterritory;R:rightcirculation;sCV:symptomaticcerebralvasospasm.a
ByaccidentIANinjectedintherightICAforafewsecondscausingtransientdropinbloodpressure.Thetreatmentis
repeatedwiththesamedose.
76 The Neuroradiology Journal 29(1)

7. At the three-month follow-up, another four (16%)
patients showed a favourable outcome (mRS 1–2), six
(24%) had a moderate outcome (mRS 3), and one more
(4%) had died (mRS 6). Data on the clinical evaluation
is presented in Table 2.
Observing a linear regression model (p ¼ 0.007,
adjusted R2
¼ 0.654), significant predictors of a poorer
clinical outcome (mRS 4–6) were an increased number
of affected vessels (p ¼ 0.003) and an increased number
of procedures carried out per patient (p ¼ 0.04), and the
angiographic response of IAN (p ¼ 0.01). Looking at
the time frame from symptomatic CV to confirming
angiographic CV, we saw a trend toward a poorer clin-
ical outcome with increasing time (p ¼ 0.13).
Discussion
Cerebral vasospasm following an aneurysmal SAH
continues to be a leading cause of morbidity and mor-
tality.3
We retrospectively reviewed 25 patients treated
with IAN infusions for medically refractory symptom-
atic CV, and found that IAN treatment was effective in
reducing angiographic CV in 95.1% of 41 treatment
sessions, with complete reversal in 75.6% and partial
reversal in 19.5%. However, the efficacy of treatment
was temporary, and required repeated treatment ses-
sions in 13 (52%) patients, and was not always followed
by clinical improvement. Only three (12%) patients
demonstrated an immediate clinical improvement
after treatment, and only one (4%) had a good clinical
outcome at the time of discharge. Eight (32%) of nine
deceased patients died during hospitalization. At three-
month follow-up, another four (16%) patients showed
a clinical improvement, while one (4%) more had died.
Overall, five (20%) patients had a favourable long-term
outcome (mRS 0–2), 10 (40%) had moderate to poor
outcome (mRS 3–5), and 10 (40%) patients had died
(mRS 6) (Table 2).
Figure 1. Patient no. 24. Lateral angiogram of the internal
cerebral artery (ICA) showing (a) cerebral vasospasm (CV);
(b) after intra-arterial nimodipine (IAN) infusion, an increase
in diameter of the vessels is observed.
Figure 2. Patient no. 12. Anteroposterior angiograms of (a) the left and (b) right internal cerebral arteries (ICAs) showing cerebral
vasospasm (CV). After intra-arterial nimodipine (IAN) infusion, (c) the left side demonstrates an increase in diameter of the vessels, while
(d) the right side shows a mixed response.
Bashir et al. 77

8. Several clinical trials have evaluated the efficacy of
IAN treatment for symptomatic CV.12–18
These studies
have reported post-IAN angiographic vessel dilatation
in 43.3–82.8% of sessions, clinical improvement in
11.1–88.9% of patients, and 61.1–88.9% with a favour-
able short- or long-term outcome (Table 3). Biondi
et al.12
were the first to assess the efficacy of IAN.
The authors reported post-IAN angiographic response
in 13 (43.3%) of 30 treatment sessions and clinical
improvement in 19 (76%) of 25 patients. Eighteen
(72%) had a favourable long-term outcome (mRS
0–2). Their angiographic results are in line with our
study. We reported complete reversal of angiographic
CV in 75.6% of sessions, and in addition partial rever-
sal of CV was seen in 19.5%. However, our angio-
graphic results did not correlate with the clinical
improvement and the overall clinical outcome was
less satisfactory, compared to Biondi et al.12
Ha¨ nggi
et al.15
investigated the efficacy of IAN in 26 patients
as well. In eight (31%) patients, no angiographic
improvement was seen, and therefore these were
excluded from the study. Using cerebral perfusion CT
(PCT), the authors reported an improved time to peak
and mean transit time a day after the procedure.
Although the efficacy of IAN was transient, and 11
(61%) of 18 patients developed additional infarction,
11 (61%) patients revealed a good clinical condition at
time of discharge, which is remarkable compared to our
study. However, some of these studies are confounded
by the combined use of IAN and papaverine or balloon
angioplasty, which might explain in part for the clinical
improvement reported in the studies.14–16
We are the second group of researchers to evaluate
the influence of time delay in diagnosing and instituting
the IAN treatment after onset of symptomatic CV. In
our study, an increasing time delay from symptomatic
CV to angiographic CV showed a trend toward a
poorer outcome with a median time of 14.5 h. The
median delay time from angiographic CV to the IAN
treatment was 3.0 h. Grotenhuis et al.23
was the first to
report that the IAN treatment was ineffective when
administrated only a few hours after the onset of CV.
However, the authors used only small dosage of nimo-
dipine ranging from 0.068–1.0 mg, which could account
at least in part for the observed lack of effect. Biondi
et al.12
performed the diagnostic CTA and IAN treat-
ment within 24 h of onset of symptomatic CV, with the
mean delay time of 18 Æ 6 h. The dosage of IAN per
vessel consisted of 1–3 mg. Despite time delay in the
diagnostic process, thus instituting the treatment, the
authors demonstrated a clinical improvement in 76%
of patients after IAN. Similarly, Linfante et al.7
inves-
tigated the efficacy of IA nicardipine in 22 patients. A
total of 46 endovascular sessions with intra-arterial
nicardipine were performed within 48 h after onset of
symptoms in 21 patients, and within 72 h in one patient.
At the time of discharge, half of patients were reported
to be independent functionally (mRS 0–2). In our
study, time delays were much less than reported by
Table3.Studieswithcerebralvasospasm(CV)afteraneurysmalsubarachnoidhaemorrhage(SAH)andintra-arterialnimodipine(IAN)treatment.
Author/yearStudydesign
Patient
no.
Session
no.
Doseof
IANpervessel
Angiographic
improvement
Clinical
improvement
Theclinical
outcome(mRS2and
GOS!4)atdischarge
Theclinicaloutcome
(mRS2andGOS!4)
atfollow-up
Biondietal.,20041,2
Retrospective25301–3mg43.3%76%–72%
Choetal.,20111,3
Retrospective421013–6mg82.2%68.3%76.2%84.6%
Dehdashtietal.,201114
Retrospective10151–4mg80%60%–70%
Ha¨nggietal.,200815,a
Prospective18260.8–3.2mg77.3%11.1%61.1%61.1%
HuiandLau,20051,6,b
Retrospective9102–4mg66.6%88.9%88.9%77.8%
Kimetal.,20091,7
Retrospective19531–3mg79.2%68.4%78.9%–
Kimetal.,201218
Prospective29291–3mg82.8%72.4%75.9%–
Ourstudy,2015Retrospective28451–4mg95.6%21.4%10.7%28.6%
GOS:GlasgowOutcomeScale;mRS:modifiedRankinscale.a
Only18of26patientsand22of42proceduresareincludedintheanalysisduetonomeasurableangiographiceffectin20(47.6%)proceduresamongeight(30.7%)
patients.b
Themeanpercentageincreaseinarterialdiameter.Angiographicimprovementincludesresultswithmoderateandmajoreffect.
78 The Neuroradiology Journal 29(1)

9. Biondi et al.12
and Linfante et al.7
and with a dosage of
IAN per vessel (range, 1–4 mg) similar to Biondi et al.12
However, despite angiographic response in 95.1% of
treatment sessions only a few patients showed clinical
improvement. The discrepancy between angiographic
response and unsatisfactory clinical results could be
explained by the fact that parenchymal damage has
already occurred due to ischaemia resulting from CV
in spite of angiographic response to endovascular treat-
ment with IAN. Furthermore, evidence from a rat
model indicated that reperfusion of parenchyma
injured by an ischaemic insult might lead to further
injury;24–26
this phenomenon could be one of the rea-
sons why the uses of endovascular therapies are asso-
ciated with a poorer outcome despite substantial vessel
dilatation in some instances, as seen in our study.
TCD is often used as a surrogate diagnostic tool to
detect CV. We found no correlation between flow-velo-
cities and angiographic responses to IAN, although
data of TCD measurements was missing in most
cases. Kim et al.17
observed a decrease in flow-velocity
in 29 of 33 sessions. In contrast, Ha¨ nggi et al.15
noticed
a significant increase in flow-velocity one day after IAN
infusion (p ¼ 0.03). Wolf et al.27
was unable to detect
CV with TCD in two patients and reflect the treatment
course in four patients. The interpretation of the TCD
analysis leaves some room for speculation. Estimation
of flow-velocity could vary from minute to minute, and
might be influenced by anatomic details such as vascu-
lar anatomy, vessel diameters and cerebral blood flow.
Influence of pathological conditions such as an
increased intracranial pressure or oedema, or systemic
haemodynamic effects during triple-H therapy such as
changes in cardiac output or blood pressure could
affect the speed and waveform of cerebral blood flow
as well. In addition, the accuracy of this technique is
quite operator-dependent with high intra-variability,
and suboptimal insonation might inhibit the detection
of high flow-velocities.28–30
Vora et al.31
reported that
only very low or very high MCA velocities (e.g.
<120 cm/s or >200 cm/s) negatively or positively pre-
dicted angiographic and symptomatic CV in a reliable
manner, and intermediate velocities had a lower pre-
dictive value and were poorly discriminative.
Vasodilatation by intra-arterial drug infusion also
has been performed with other agents. Papaverine is
the first intra-arterial agent reported to reverse angio-
graphic CV.6
However, it is associated with a consider-
able number of several adverse side effects such as
elevation of intracranial pressure,32
worsening of
CV33
and thrombocytopaenia.34
One study compared
the angiographic effect of papaverine and nimodipine
and reported that there was no significant difference
between these two groups, although the effect of papa-
verine was more pronounced, dilating at least one vessel
in every patient, while nimodipine was ineffective in
16% of patients.35
Intra-arterial nicardipine infusion
has shown to be effective without increasing intracra-
nial pressure.36
However, a transient decrease in blood
pressure and an increase in heart rate may occur.7,36
Intra-arterial verapamil infusion is also reported to
dilate spastic vessels without causing changes in
haemodynamic circulation or intracranial pressure.6
However, it needs to be evaluated in larger series to
confirm its efficacy. PTA is highly effective in relieving
focal CV, and has a continuous effect on narrowed ves-
sels. However, the technique is limited to proximal ves-
sels, and requires expert neurointerventionists due to
the significant risks of artery rupture, dissection and
local thrombosis.19,37
One study compared the clinical
outcome of IAN treatment with PTA, but the authors
did not find significant differences in these two
groups.38
Limitations
The study has several important limitations including
its retrospective design and the small number of
patients due to it being a single centre study, which
may limit generalizability. There was no control
group. It is not clear whether the change in the clinical
condition after IAN infusion was due to the effect of
the treatment or just a natural course. Quantitative
measurement of vessel diameter on pre- and post-
nimodipine angiograms was not available as mm
(Æstandard deviation), but only as Æeffect. TCD data
were missing before and after IAN infusions in several
patients making it more difficult to estimate the abso-
lute correlation between TCD and angiographic results.
Data on monitoring systemic haemodynamic effects
and intracranial pressure during IAN sessions were
not investigated, and therefore we were unable to quan-
tify the effect of IAN on these areas.
Conclusion and perspectives
Although there are several limits in this retrospective
study, we can conclude that IAN treatment appears to
be effective in reversing angiographic CV. However, the
relationship between angiographic and clinical
responses was not convincing, as the treatment is inef-
fective in reversing clinical deterioration caused by
DCI. Several factors such as increased numbers of
affected vessels and procedures carried out per patient
predicted the clinical outcome negatively. In addition, an
increasing time delay in diagnostic process of CV and
thus instituting treatment might contribute to a poorer
clinical outcome. Clearly, early detection and rapid
treatment of CV are needed before ischaemic damage
occurs. Future studies with continued assessment of
cerebral blood flow might help optimize the timing of
IAN treatment and to assess the real efficacy of the IAN
treatment in patients with symptomatic CV after SAH.
Acknowledgements
The study is dedicated to the late Professor Bertil Romner,
Department of Neurosurgery, Rigshospitalet, who originally
conceived and designed the study. A Bashir and the late
Bashir et al. 79

10. Bertil Romner conceived and designed the study. A Bashir
reviewed patient data and wrote the first and subsequent
drafts of the manuscript. A Wagner and M Cortsen evaluated
pre- and post-angiograms. M Andresen conducted the statis-
tical analysis. J Bartek Jr, M Andresen, A Wagner, M
Cortsen and V Eskesen participated in critical revision and
writing of the article. All authors have seen and approved the
final version.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Conflict of interest
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
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