original papers

Adv Clin Exp Med 2013, 22, 1, 101–109 © Copyright by Wroclaw Medical University
ISSN 1899–5276

Milan Mijailovic1, A, D–F, Snezana Lukic1, A, D–F, Dragomir Laudanovic2, B, C, F,

Marko Folic3, C–F, Nevena Folic3, C–F, Slobodan Jankovic3, A, C–F

Effects of Nimodipine on Cerebral Vasospasm

in Patients with Aneurysmal Subarachnoid
Hemorrhage Treated by Endovascular Coiling*
Wpływ nimodypiny na skurcz naczyń mózgowych
u chorych z krwotokiem podpajęczynówkowym z pękniętego tętniaka
leczonych przez embolizację wewnątrznaczyniową
1
Radiology Department, Medical Faculty, University of Kragujevac and Kragujevac Clinical Center, Kragujevac, Serbia
2
Radiology Department, City Hospital, Uzice, Serbia
3
Pharmacology Department, Medical Faculty, University of Kragujevac and Kragujevac Clinical Center,
Kragujevac, Serbia

A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of article; G – other

Abstract
Background. An aneurysmal subarachnoid hemorrhage could be complicated with cerebral vasospasm and resul-
tant ischemia, causing neurological deficit.
Objectives. The aim of this study was to compare early and late outcomes in patients with subarachnoidal hem-
orrhage (SAH) treated by endovascular coiling, who either received or did not receive prophylaxis of cerebral
vasospasm with nimodipine.
Material and Methods. In this retrospective cross-sectional study, the data was collected from the histories of 68
patients (38 females and 30 males, age range 29–71 years) with spontaneous aneurysmal SAH in clinical stage HH
I–IV, treated at Kragujevac Clinical Center, Serbia, from January 2008 till June 2009. The study population was
divided into two groups: (1) the group of 42 patients who received intravenous prophylaxis with nimodipine for
3 weeks, and (2) the group of 26 patients who did not receive nimodipine prophylaxis.
Results. Prophylactic use of nimodipine did not decrease the rate of neurological deficit after one month, but
the rates of both cerebral vasospasm (symptomatic and asymptomatic) and the morphological signs of ischemia
using nuclear magnetic resonance imaging (MRI) were significantly lower in the nimodipine-protected group.
Cerebral vasospasm was detected by Digital Subtraction Angiography (DSA) in the group protected by nimodipine
as discrete in 2 patients (5%), and as apparent in 0 patients (0%). On the other hand, in the group unprotected by
nimodipine, cerebral vasospasm was detected by DSA as discrete in 9 patients (35%), and as apparent in 6 patients
(23%). Up to one month after the endovascular coiling, in the nimodipine-protected group, the T1W hypointense
zones were detected by MRI as “small” in 5 patients (12%), as “medium” in 1 patient (2.5%), as “large” in 1 patient
(2.5%), and as “multiple” in 2 patients (5%). In the nimodipine-unprotected group, the T1W hypointense zones
were detected by MRI as “small” in 4 patients (16%), as “medium” in 2 patients (8%), as “large” in 3 patients (12%),
and as “multiple” in 4 patients (16%). The difference between the groups was significant.
Conclusions. When a patient with SAH is treated with the endovascular clipping procedure, prophylactic admin-
istration of nimodipine is mandatory due to the reduced rate of cerebral vasospasm and delayed cerebral ischemia
(Adv Clin Exp Med 2013, 22, 1, 101–109).
Key words: subarachnoidal hemorrhage, endovascular coiling, cerebral vasospasm, nimodipine.

* This study was partially funded through a grant awarded by the Medical Faculty, University of Kragujevac, and
through a grant given by the Montenegro Ministry of Science.
102 M. Mijailovic et al.

Streszczenie
Wprowadzenie. Krwotok podpajęczynówkowy może być powikłany skurczem naczyń mózgowych i następującym
niedokrwieniem, co powoduje deficyt neurologiczny.
Cel pracy. Porównanie wyników wczesnych i  odległych u  chorych z  krwotokiem podpajęczynówkowym (SAH)
leczonych przez embolizację wewnątrznaczyniową, którzy otrzymali lub nie otrzymywali nimodypinę jako profi-
laktykę skurczu naczyń mózgowych.
Materiał i metody. W tym retrospektywnym badaniu przekrojowym zebrano historie 68 pacjentów (38 kobiet i 30
mężczyzn, w wieku 29–71 lat) ze spontanicznym krwotokiem podpajęczynówkowym z pękniętego tętniaka w kli-
nicznym stadium HH I-IV, leczonych w Centrum Klinicznym w Kragujevac, Serbia, od stycznia 2008 do czerwca
2009 roku. Badanych podzielono na dwie grupy: (1) grupa 42 pacjentów, którzy otrzymywali dożylnie profilaktycz-
nie nimodypinę przez 3 tygodnie i (2) grupa 26 pacjentów, którzy nie otrzymywali nimodypiny.
Wyniki. Profilaktyczne stosowanie nimodypiny nie zmniejszyło odsetka deficytu neurologicznego po miesiącu,
ale częstotliwość zarówno skurczu naczyń mózgowych (objawowego i  bezobjawowego), jak i  morfologicznych
objawów niedokrwienia w badaniu MRI były istotnie mniejsze w grupie, w której podawano nimodypinę. Skurcz
naczyń mózgowych został wykryty za pomocą badania DSA w grupie, w której podawano nimodypinę jako niecią-
gły u 2 (5%), i jako widoczny u 0 pacjentów (0%). Z drugiej strony, w grupie bez podawania nimodypiny, skurcz
naczyń mózgowych wykryto za pomocą metody DSA jako nieciągły u 9 pacjentów (35%), i widoczny u 6 pacjentów
(23%). W ciągu jednego miesiąca po embolizacji wewnątrznaczyniowej w grupie, w której podawano nimodypi-
nę hipointensywne obszary T1W zostały wykryte w badaniu MR jako „małe” u 5 chorych (12%), jako „średnie”
u 1 chorego (2,5%), jako „duże” u 1 (2,5%), jako „liczne” u 2 (5%). W grupie bez podawania nimodypiny, hipointen-
sywne obszary T1W wykryte w badaniu MR jako „małe” u 4 (16%), jako „średnie” u 2 (8%), jako „duże” u 3 (12%),
i jako „liczne” u 4 chorych (16%). Różnica między grupami była istotna statystycznie.
Wnioski. Kiedy pacjent z  krwotokiem podpajęczynówkowym jest leczony za pomocą embolizacji wewnątrzna-
czyniowej, profilaktyczne podawanie nimodypiny jest obowiązkowe ze względu na zmniejszenie ryzyka skurczu
naczyń mózgowych i opóźnianie niedokrwienia mózgu (Adv Clin Exp Med 2013, 22, 1, 101–109).
Słowa kluczowe: krwotok podpajęczynówkowy, embolizacja wewnątrznaczyniowa, skurcz naczyń mózgowych,
nimodypina.

An aneurysmal subarachnoid hemorrhage
(SAH) could be complicated with cerebral vaso-
spasm, which adversely affects the outcome: it ac-
counts for up to 23% of disability and deaths related
to SAH [1–5]. Although the incidence of vasospasm
ranges from 40% to 70% of aneurismal SAH patients
(vasospasm documented by angiography), it causes
symptoms due to delayed ischemic neurological
deficit (DID) (symptomatic vasospasm) in only
17–40% of patients with aneurismal SAH [6–9].
However, every second patient with symptomatic
vasospasm will develop ischemic infarct [10].
SAH-induced vasospasm is a  complex and
poorly understood entity due in part to a delayed
and reversible vasculopathy, impaired autoregula-
tory function, and hypovolemia causing regional
reduction of cerebral perfusion to the point of
causing ischemia [11, 12]. Histologically, there
are structural alterations in the endothelial and
smooth muscle cells of the arterial wall [13]. The
presence of oxyhemoglobin in subarachnoid space
seems to be a  triggering event, necessary to pro-
duce these changes [14–16]. However, the spe-
cific mechanisms leading to vasoconstriction are
not completely identified. In vitro, oxyhemoglo-
bin stimulates secretion of potent vasoconstrictor
endothelin-1  in endothelial cells, inhibits the va-
sodilator nitric oxide (NO) and produces reactive
oxygen species, leading to lipid peroxidation and
structural changes in the vessels [17–19].
Risk factors for vasospasm and DID are the
amount and duration of exposure to subarach-
noid blood and presence of blood in cerebral ven-
tricles [20–23]. Interestingly, endovascular coiling
of the ruptured aneurysm, a  procedure that does
not involve a craniotomy and washing out of the
subarachnoid blood, does not increase the risk of
vasospasm in comparison to surgical clipping [24,
25]). Advanced age [26], race [27], poor neurolog-
ical status on admission [5, 26, 28] and use of an-
tifibrinolytic agents [4, 22, 29] are also associated
with the development of DID. Factors less strongly
linked to a  higher incidence of DID are a  longer
duration of unconsciousness following the initial
hemorrhage [30], history of hypertension [26, 31],
smoking [32, 33] and excess weight [31].
Nimodipine is a  dihydropyridine derivative
that blocks calcium influx through the L-type
calcium channels. It is well studied and the only
drug approved by drug agencies in the majority
of countries for use in the prevention and treat-
ment of cerebral vasospasm. It has been shown in
clinical studies to be a safe [34] and cost-effective
drug [35–39] when cerebral vasospasm itself was
the main outcome; however, its effectiveness has
remained unclear when mortality and neurologi-
cal sequelae were studied as the main outcomes
[36–39]. On the other hand, prevention of cerebral
vasospasm and DID by nimodipine in patients af-
ter aneurismal SAH treated by endovascular coil-
Cerebral Vasospasm and Nimodipine
ing has rarely been studied in larger patient series
[40], and was never compared with non-preven-
tion in the same study period, due to ethical rea-
sons. However, in hospitals without established
local protocols for administration of nimodipine
after SAH, it may happen that a certain percentage
of patients remain unprotected by this drug, giving
an opportunity to study cerebral vasospasm and
DID after endovascular coiling itself.
The aim of this study was to investigate the ef-
fect of nimodipine on the prevention of cerebral
vasospasm and DID in patients with SAH treated
by endovascular coiling, comparing patients who
received nimodipine prophylaxis with those who
did not .
Material and Methods
Study Design
This study was designed as a  retrospective
cross-sectional study, including all patients hospi-
talized at the study site due to aneurysmal SAH
during a pre-defined time period.
Patient Population
During the time period from January 2008 till
June 2009, there were 68 patients (38 females and
30 males, age range 29–71 years) with spontane-
ous aneurysmal SAH in clinical stage HH I–IV,
treated at Kragujevac Clinical Center, in Kraguje-
vac, Serbia. The diagnosis of SAH was confirmed
by the evidence of blood in the subarachnoid space
during computerized tomography (CT) scans. All
patients were subjected to endovascular coiling of
the ruptured aneurysm. During the endovascular
procedure, if cerebral vasospasm was induced, an
intraarterial bolus injection of 0.4 mg nimodipine
was administered.
Characteristics of the patient population are
listed in Table 1.
Nimodipine Prophylaxis
In 42 patients with aneurysmal SAH, nimo-
dipine was administered prophylactically im-
mediately after the diagnosis was confirmed. Ni-
modipine was given as a  continuous intravenous
infusion in a daily dose of 60 mg daily during the
first week, 40 mg daily in the second week and 20
mg daily in the third week. In 26 patients, nimo-
dipine was not administered prophylactically, by
individual decision of the responsible physician.
This study revealed such an obsolete practice,
and served as the background for adoption and
103
implementation of local guidelines for the obliga-
tory prophylactic administration of nimodipine in
the year 2009. The study patients were followed
by a  neurologist and neuroradiologist up to nine
months from SAH onset.
Study Outcomes
The main study outcomes were cerebral va-
sospasm, delayed ischemic neurological deficit
and incidence of cerebral infarction. The cerebral
vasospasm was diagnosed by Digital Subtracting
Angiography (DSA) or by Nuclear Magnetic Reso-
nance (MRI) diffusion. Delayed ischemic neuro-
logical deficit was diagnosed by MRI, and cere-
bral infarction was confirmed by the presence of
T1W hypointense zones accompanied with focal
neurological deficits appropriate for those zones.
The T1W hypointense zones were classified by
the same observer radiologist on a visual analogue
scale (with a range from 0 to 10) as “small“ (values
0–4), “medium“ (values 5, 6  and 7), and “large“
(values 8–10). The patients were evaluated on the
first, third and seventh day after endovascular coil-
ing, and then after one, three and nine months.
Statistics
The characteristics of the study groups are de-
scribed with frequencies (for discrete variables) or
with mean values ± standard deviation (for con-
tinuous variables). The significance of differences
between groups was tested by Chi-square test (for
frequencies) or by Student’s T-test for small inde-
pendent samples (for continuous variables). When
less than 80% of observed frequencies are greater
than 5, the Fisher exact probability test was used
for comparison between the study groups. A com-
parison of two groups of paired observations for
frequencies was made using a McNemar test. The
differences were considered significant if the prob-
ability of the null hypothesis was less than 0.05.
Calculations of the Chi-square test and Fisher ex-
act probability test were made using online inter-
active calculation tools [41, 42]), while calculations
of the Student’s  T-test and McNemar test were
made manually.
Results
The endovascular coiling procedure in this
study led to a  significant decrease in aphasia fre-
quency (χ2McNemar = 5.818, p < 0.05). Before the pro-
cedure, 38 patients (56%) experienced aphasia, and
one month after endovascular coiling only 14 pa-
tients (21%) still had aphasia at a neurological eval-
104 M. Mijailovic et al.

Table 1. Baseline characteristics of the study groups. For discrete variables, figures in the table show absolute number of
patients and percentage of the total number of patients in the respective group in parentheses
Tabela 1. Charakterystyka wyjściowa badanych grup. Dla zmiennych dyskretnych dane w tabeli pokazują bezwzględną liczbę
pacjentów i odsetek całkowitej liczby pacjentów w danej grupie w nawiasach
Factor Group with Group without prophy- Comparison between
(Czynnik) prophylaxis with nimodipine laxis with nimodipine the groups
(Grupa z profilaktyką za (Grupa bez profilaktyki (Porównanie między
pomocą nimodypiny) za pomocą nimodypiny) grupami)
Number of patients 42 26
(Liczba pacjentów)
Sex – male/female 20/22 (48%/52%) 10/16 (38%/62%) χ2 = 0.398, p > 0.05
(Płeć)
Age – years 52 ± 10.34 54 ± 11.42 T-test = 2.445, p < 0.05*
(Wiek – lata)
Body weight – kg 73 ± 12.57 75 ± 14.78 T-test = 2.189, p < 0.05*
(Masa ciała – kg)
Smokers 32 (76%) 22 (85%) χ2 = 0.533, p > 0.05
(Palacze)
Diabetes mellitus 10 (24%) 5 (19%) χ2 = 0.216, p > 0.05
(Cukrzyca)
Hypercholesterolemia 21 (50%) 11 (42%) χ2 = 0.433, p > 0.05
(Hipercholesterolemia)
Hypertension 18 (43%) 14 (54%) χ2 = 0.317, p > 0.05
(Nadciśnienie tętnicze)
Multiple aneurisms   4 (10%)   3 (12%) χ2 = 0.416, p > 0.05
(Wiele tętniaków)
Location of aneurysm χ2 = 0.985, p > 0.05
(Umiejscowienie tętniaka)  
   internal carotid artery 12 (29%)   7 (27%)
   middle cerebral artery   8 (19%)   6 (23%)
   anterior communicating artery   6 (14%)   3 (11.5%)
   anterior cerebral artery   3 (7%)   1 (4%)
   posterior communicating artery   4 (10%)   3 (11.5%)
   vertebrobasilar circulation   6 (14%)   3 (11.5%)
   other   3 (7%)   3 (11.5%)
Interval (days) between SAH onset   3.80 ± 2.32   4.45 ± 1.75 T-test = 1.796, p > 0.05
and endovascular coiling
(Czas w dniach od rozpoczęcia
krwotoku podpajęczynówkowego
do przeprowadzenia embolizacji
wewnątrznaczyniowej)
Hunt and Hess (HH) grade χ2 = 0.763, p > 0.05
(Stopień)
I 10 (24%)   6 (23%)
II 16 (38%) 11 (42%)
III 13 (31%)   8 (31%)
IV   3 (7%)   1 (4%)
For continuous variables, mean values ± standard deviation are shown in the table.
* significant difference.
Dla zmiennych ciągłych dane są przedstawione w tabeli jako wartości średnie ± odchylenie standardowe.
* Różnica istotna statystycznie.

uation. However, the frequency of aphasia before ine prophylaxis. Before the procedure, there were
and after endovascular coiling was not significant- 24 patients (57%) with aphasia in the nimodipine
ly different in groups with and without nimodip- group, and 14 patients (54%) with aphasia in the
Cerebral Vasospasm and Nimodipine 105

Table 2. Differences in outcomes among the study groups

Tabela 2. Różnice w wynikach między grupami badanych

Factor Group with prophy- Group without prophy- Comparison

(Czynnik) laxis with nimodipine laxis with nimodipine between the groups
(Grupa z profilaktyką za (Grupa bez pro- (Porównanie między
pomocą nimodypiny) filaktyki za pomocą grupami)
nimodypiny)
Frequency of aphasia before the endo- 24 (57%) 14 (54%) χ2 = 0.071, p > 0.05
(Częstotliwość afazji) vascular coiling
after the endo-   6 (14%)   8 (31%) χ2 = 2.669, p > 0.05
vascular coiling
Frequency of motor def- before the endo- 25 (60%) 14 (54%) χ2 = 0.212, p > 0.05
icit in upper extremities vascular coiling
(Częstotliwość deficytu
ruchowego kończyn after the endo-   7 (17%)   7 (27%) χ2 = 1.033, p > 0.05
górnych) vascular coiling

Frequency of motor def- before the endo- 23 (55%) 14 (54%) χ2 = 0.005, p > 0.05
icit in lower extremities vascular coiling
(Częstotliwość deficytu
ruchowego kończyn after the endo-   6 (14%)   7 (27%) χ2 = 1.659, p > 0.05
dolnych) vascular coiling

Frequency of confusion before the endo- 28 (67%) 18 (69%) χ2 = 0.048, p > 0.05
(Częstotliwość stanu vascular coiling
splątania)
after the endo-   5 (12%)   5 (19%) χ2 = 0.484, p > 0.05
vascular coiling
Cerebral vasospasm before the endo- discrete: 4 (10%) discrete: 4 (15%) P  = 0.001462*
(Skurcz naczyń vascular coiling
mózgowych apparent: 1 (4%) apparent: 7 (27%) P  = 0.001462*
after the endo- discrete: 2 (5%) discrete: 9 (35%) P  = 0.0000008*
vascular coiling
apparent: 0 (0%) apparent: 6 (23%) P  = 0.0000008*
T1W hypointense zones before the endo- small: 2 (5%) small: 2 (8%)
detected by MRI vascular coiling χ2 = 3.410, p > 0.05
(T1W hipointensywne medium: 1 (2.5%) medium: 1 (4%)
obszary wykryte przez large: 0 (0%) large: 1 (4%)
MR)
multiple: 2 (5%) multiple: 3 (12%)
after the endo- small: 5 (12.5%) small: 4 (16%) χ2 = 5.990, p < 0.05*
vascular coiling
medium: 1 (2.5%) medium: 2 (8%)
large: 1 (2.5%) large: 3 (12%)
multiple: 2 (5%) multiple: 4 (16%)
Mortality rate 9 months after endovascular 1 (2%) 3 (11.5%) Fisher’s exact test:
coiling p  = 0.152446
(Śmiertelność 9 miesięcy po embolizacji
wewnątrznaczyniowej)
Neurological deficit 9 months after endovas- 7 (17%) 9 (39%) χ2 = 3.823, p > 0.05
cular coiling
(Deficyt neurologiczny 9 miesięcy po embo-
lizacji wewnątrznaczyniowej)
For discrete variables, figures in the table show the absolute number of patients and percentage of the total number of patients
in the respective group in parentheses. For continuous variables, mean values ± standard deviation are shown in the table.
* significant difference.
Dla zmiennych dyskretnych dane w tabeli pokazują bezwzględną liczbę pacjentów i odsetek całkowitej liczby pacjentów
w danej grupie w nawiasach.
Dla zmiennych ciągłych dane są przedstawione w tabeli jako wartości średnie ± odchylenie standardowe.
* Różnica istotna statystycznie.
106
group without nimodipine (χ2 = 0.071, p  > 0.05);
one month after endovascular coiling, there were
6  patients (14%) with aphasia in the nimodipine
group, and 8  (31%) patients with aphasia in the
group without nimodipine (χ2 = 2.669, p > 0.05).
The frequency of motor deficit in the upper
extremities was decreased by the endovascular
coiling procedure in this study (χ2McNemar = 4.667,
p < 0.05). Before the procedure, 40 patients (59%)
experienced motor deficit in upper extremities,
and one month after endovascular coiling, only 14
patients (21%) still had such a deficit at the neuro-
logical evaluation. However, the frequency of mo-
tor deficit in upper extremities before and after en-
dovascular coiling was not significantly different in
groups with and without nimodipine prophylaxis.
Before the procedure, there were 25 patients (60%)
with motor deficit in upper extremities in the ni-
modipine group, and 14 patients (54%) with motor
deficit in upper extremities in the group without
nimodipine (χ2 = 0.212, p > 0.05); one month after
endovascular coiling there were 7  patients (17%)
with motor deficit in upper extremities in the ni-
modipine group, and 7 patients (27%) with motor
deficit in upper extremities in the group without
nimodipine (χ2 = 1.033, p > 0.05).
The frequency of motor deficit in the lower
extremities was decreased by the endovascular
coiling procedure in our study (χ2McNemar=7.364,
p<0.01). Before the procedure 37 patients (54%)
experienced motor deficit in lower extremities,
and one month after endovascular coiling only
13 patients (19%) still had such a  deficit at the
neurological evaluation. However, the frequency
of motor deficit in lower extremities before and
after endovascular coiling was not significantly
different in groups with and without nimodipine
prophylaxis. Before the procedure there were 23
patients (55%) with motor deficit in lower ex-
tremities in the nimodipine group, and 14 patients
(54%) with motor deficit in lower extremities in
the group without nimodipine (χ2=0.005, p>0.05);
one month after endovascular coiling there were
6  patients (14%) with motor deficit in lower ex-
tremities in the nimodipine group, and 7 patients
(27%) with motor deficit in lower extremities in
the group without nimodipine (χ2=1.659, p>0.05).
The endovascular coiling procedure in this
study led to a  significant decrease of confusion
frequency (χ2McNemar = 4.500, p < 0.05). Before the
procedure, 46 patients (68%) were confused, and
one month after endovascular coiling only 10 pa-
tients (15%) still were confused at the neurologi-
cal evaluation. However, the frequency of confu-
sion before and after endovascular coiling was not
significantly different in groups with and without
nimodipine prophylaxis. Before the procedure,
M. Mijailovic et al.
there were 28 patients (67%) with confusion in
the nimodipine group, and 18 patients (69%) with
confusion in the group without nimodipine (χ2
= 0.048, p > 0.05); one month after endovascular
coiling, there were 5  patients (12%) with aphasia
in the nimodipine group, and 5  patients (19%)
with confusion in the group without nimodipine
(χ2 = 0.484, p > 0.05).
Throughout the whole hospital treatment of
the patients, symptomatic vasospasm appeared
more often in the group without nimodipine (in
12 patients out of 26, or 46%) than in the group
protected by nimodipine (in 5 patients out of 42,
or 12%), and this difference was significant (χ2 =
10.046, p < 0.01).
Before the endovascular coiling, cerebral vasos-
pasm detected by Digital Subtracting Angiography
in the group protected by nimodipine was charac-
terized as discrete in 4  patients (10%), and as ap-
parent in 1 patient (4%). On the other hand, in the
group unprotected by nimodipine, cerebral vasos-
pasm was detected by DSA as discrete in 4 patients
(15%), and as apparent in 7  patients (27%). The
difference between the groups in frequency of cere-
bral vasospasm before the endovascular coiling was
significant (Fisher exact test with Freeman-Halton
extension: PA = 0.001462, PB = 0.001462).
Up to one month after the endovascular coil-
ing, cerebral vasospasm was detected by Digital
Subtracting Angiography in the group protected by
nimodipine as discrete in 2 patients (5%), and as ap-
parent in 0 patients (0%). On the other hand, in the
group unprotected by nimodipine, cerebral vasos-
pasm was detected by DSA as discrete in 9 patients
(35%), and as apparent in 6  patients (23%). The
difference between the groups in frequency of ce-
rebral vasospasm after the endovascular coiling was
significant (Fisher exact test with Freeman-Halton
extension: PA = 0.0000008, PB = 0.0000008).
If nimodipine prophylaxis is not taken into
account, out of 68 study patients total, there were
8  (12%) with discrete and 8  (12%) with apparent
cerebral vasospasm before the endovascular coiling,
and 11 (16%) with discrete and 6 (9%) with appar-
ent cerebral vasospasm up to one month after the
endovascular coiling. The difference in rate of cere-
bral vasospasm before and after endovascular coil-
ing was not significant (χ2McNemar = 0.769, p > 0.05).
There were in total 20 cases (29%) of cerebral
vasospasm induced by the endovascular coiling
procedure, regardless of the nimodipine prophy-
laxis. Twelve cases were classified as “mild“, and
8 as “severe“. Intraarterial injection of nimodipine
during the procedure successfully reversed vasos-
pasm in 4  “mild“ cases (33%), and in 6  “severe”
cases (75%).
Before the endovascular coiling, in the nimo-
Cerebral Vasospasm and Nimodipine
dipine-protected group, the T1W hypointense zones
were detected by MRI as “small“ in 2 patients (5%), as
“medium“ in 1 patient (2.5%), as “large“ in 0 patients,
and as “multiple“ in 2 patients (5%). In the nimodipine-
unprotected group, the T1W hypointense zones were
detected by MRI as “small“ in 2 patients (8%), as “me-
dium“ in 1 patient (4%), as “large“ in 1 patient (4%),
and as “multiple“ in 3  patients (12%). However, the
difference between the groups in frequency of the
T1W hypointense zones (the subgroups merged) was
not significant (χ2 = 3.410, p > 0.05).
Up to one month after the endovascular coil-
ing, in the nimodipine-protected group, the T1W
hypointense zones were detected by MRI as “small“
in 5  patients (12.5%), as “medium“ in 1  patient
(2.5%), as “large“ in 1 patient (2.5%), and as “mul-
tiple“ in 2  patients (5%). In the nimodipine-un-
protected group, the T1W hypointense zones were
detected by MRI as “small“ in 4 patients (16%), as
“medium“ in 2  patients (8%), as “large“ in 3  pa-
tients (12%), and as “multiple“ in 4 patients (16%).
The difference between the groups in frequency
of the T1W hypointense zones (the subgroups
merged) was significant (χ2 = 5.990, p < 0.05).
If nimodipine prophylaxis is not taken into ac-
count, out of 68 study patients total, there were
“small“ T1W hypointense zones in 4 patients (6%),
“medium“ in 2  patients (3%), “large“ in 1  patient
(1.5%), and “multiple“ 5  patients (7.5%) before the
endovascular coiling, and “small“ T1W hypointense
zones in 9 patients (13.5%), “medium“ in 3 patients
(4.5%), “large“ in 4  patients (6%), and “multiple“
6 patients (9%) up to one month after the endovas-
cular coiling. The difference in frequency of T1W hy-
pointense zones before and after endovascular coil-
ing was not significant (χ2McNemar=3.457, p > 0.05).
Finally, nine months after the endovascular
coiling, in the nimodipine-protected group there
was one case of death due to SAH (2% mortality)
and 7 patients with any kind of neurological defi-
cit (17%). In the nimodipine-unprotected group,
there were 3  cases of death due to SAH (11.5%
mortality) and 9 patients with any kind of neuro-
logical deficit (39%). The difference between the
groups in the rate of neurological deficit was not
significant (χ2 = 3.823, p  > 0.05). The difference
between the groups in mortality rate was also not
significant (Fisher’s exact test: p = 0.152446).
Discussion
Of the two most significant complications after
subarachnoid hemorrhage (SAH), rebleeding and
delayed cerebral ischemia, the first is effectively
prevented by neurosurgical clipping or endovas-
cular obliteration of ruptured aneurysms [43]. For
107
prevention of the second complication, oral or in-
travenous nifedipine is used; however, the relation
between the prevention of cerebral vasospasm/
delayed cerebral ischemia and the improvement
of long-term patient outcomes is not completely
clear. In a  recent study with 232 subarachnoid
hemorrhage survivors, the frequency of neuro-
logical sequelae after one year from SAH was only
loosely related to cerebral vasospasm and delayed
cerebral ischemia (3.6 times greater risk) [44].
In this study, the endovascular coiling procedure
by itself decreased the rate of neurological deficit in
the short term (decreased rate of aphasia, motor
deficit in lower and upper extremities, and confu-
sion after one month), but this was not accompanied
by a decreased frequency of morphological signs of
ischemia in an MRI of the brain (T1W hypointense
zones) or decreased rate of cerebral vasospasm. On
the contrary, the endovascular coiling procedure may
induce cerebral vasospasm [45], requiring immediate
intra-arterial administration of nimodipine. Twenty-
nine percent of present patients developed cerebral
vasospasm during the endovascular procedure, and
intraarterial nimodipine successfully reversed the va-
sospasm in the majority of cases. Similar results were
obtained in other studies, achieving reversal of vaso-
spasm in three-fourths of cases [46].
On the other hand, prophylactic use of nimo-
dipine did not decrease the rate of neurological
deficit after one month, but the rates of both cere-
bral vasospasm (symptomatic and asymptomatic)
and morphological signs of ischemia in an MRI
were significantly lower in the nimodipine-pro-
tected group. In other studies [40], the beneficial
effect of nimodipine on cerebral vasospasm was
also observed in patients with SAH treated by neu-
rosurgical clipping of ruptured aneurysms, further
strengthening the recommendation to use nimo-
dipine in all cases of SAH, regardless of the meth-
od used for mechanical prevention of rebleeding.
In this study, prophylactic use of nimodipine
did not affect the long-term outcomes of SAH, like
mortality and the rate of neurological sequelae af-
ter nine months, although there was a  tendency
towards improvement of the sequelae. Similar
results were observed in a recent study [47], con-
firming present findings, but one early study [34]
did relate nimodipine use with better neurological
outcome after 3 months. It seems that the preven-
tion of cerebral vasospasm and delayed cerebral
ischemia achieved by nifedipine prophylaxis does
not translate directly into improvement of func-
tional neurological impairment. There are alterna-
tive causes of neurological deterioration and poor
outcome after SAH, such as the delayed effects of
acute global cerebral ischemia, thromboembolism
and microcirculatory dysfunction [48]. Cerebral
108 M. Mijailovic et al.

vasospasm probably just initiates complex pro-
cesses in brain tissue, leading eventually to loss of
function. In order to improve the final outcomes
after SAH, it is not enough to prevent or reverse
cerebral vasospasm; additional therapy is needed
to prevent or reverse the adverse processes which
impair microcirculation and oxygen transport
within the brain areas affected by vasospasm.
When a patient with SAH is treated with the
endovascular clipping procedure, prophylactic ad-
ministration of nimodipine is mandatory due to
the reduced rate of delayed cerebral ischemia. If
such a patient develops vasospasm during the en-
dovascular coiling procedure, intraarterial admin-
istration of nimodipine will reverse the vasospasm
with high probability. However, further studies are
needed to search for additional therapeutic mea-
sures which will improve the final outcome of pa-
tients with SAH.

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Address for correspondence:

Slobodan M. Jankovic
Medical Faculty, University of Kragujevac
ul. Svetozara Markovica 69 Conflict of interest: None declared
34000 Kragujevac
Serbia Received: 3.11.2011
Tel.: +381 61 320 63 92 Revised: 22.04.2012
E-mail: slobodan.jankovic@medf.kg.ac.rs Accepted: 11.02.2013