J Neurosurg 110:5863, 2009

58 J. Neurosurg. / Vol 110 / January, 2009

A
NEURYSMAL SAH remains a stroke subtype with
high morbidity and mortality rates despite consid-
erable advances in its diagnosis and management
during the last decade.
27
A major reason for an unfavor-
able outcome following SAH is DIND caused by arterial
cerebral vasospasm typically developing between 4 and
10 days after ictus.
4,12,21
Poor outcome (death or depen-
dence) has been reported in 70% of the patients who have
suffered an SAH, and it has been estimated that a DIND
is implicated in ~ one-third of these cases.
3,13
The pathophysiological mechanism underlying SAH-
related vasospasm is largely unknown, and medical treat-
ment has so far failed to prevent its occurrence. Treatment
options include hypervolemia, hemodilution, and induced
hypertension (so-called triple-H therapy); calcium antago-
nists; and angioplasty.
16
Based on the hypothesis that va-
sospasm is at least partially dependent on calcium infux in
vascular smooth-muscle cells, the dihydropyridine calcium
antagonist nimodipine was introduced during the 1980s as
a prophylactic treatment in patients who experienced an
SAH. Randomized trials have demonstrated that treatment
with nimodipine reduces the proportion of patients with
DIND and poor outcome as well as the number of cerebral
infarctions
3,19
and that this treatment is cost-effective.
11
It
is now common practice in most centers to administer ni-
modipine to all patients who have had an SAH. Because
most trials have been conducted with peroral administra-
tion of the drug, this route has become the most common.
However, despite the fact that the intravenous administra-
tion of nimodipine can induce arterial hypotension, is sub-
stantially more expensive, and has not proven benefcial
in randomized trials, several centers routinely administer
Nimodipine in aneurysmal subarachnoid hemorrhage:
a randomized study of intravenous or peroral administration
Clinical article
Erik kronvall, M.D.,
1
PEr UnDrn, M.D.,
2
BErtil roMnEr, M.D., Ph.D.,
1

hans svElanD, M.D., Ph.D.,
1
Mats Cronqvist, M.D., Ph.D.,
2

anD ola G. nilsson, M.D., Ph.D.
1
Departments of
1
Neurosurgery and
2
Neuroradiology, Lund University Hospital, Lund, Sweden
Object. The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications
following aneurysmal subarachnoid hemorrhage (SAH). Although most randomized studies have been focused on
the effect of the peroral administration of nimodipine, intravenous infusion is an alternative and the preferred mode
of treatment in many centers. It is unknown whether the route of administration is of any importance for the clinical
effcacy of the drug.
Methods. One hundred six patients with acute aneurysmal SAH were randomized to receive either peroral or
intravenous nimodipine treatment. The patients were monitored for at least 10 days after bleeding in terms of delayed
ischemic neurological defcits (DINDs) and with daily measurements of blood fow velocities in the middle cerebral
arteries by using transcranial Doppler ultrasonography. Three months after SAH, clinical outcome and new cerebral
infarctions according to MR imaging studies were recorded.
Results. Baseline characteristics (age, sex distribution, clinical status on admission, radiological fndings, and
aneurysm treatment) did not differ between the treatment groups. There was no signifcant difference in the incidence
of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood fow veloc-
ities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the
same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging.
Conclusions. The results suggest that there is no clinically relevant difference in effcacy between peroral and
intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.
(DOI: 10.3171/2008.7.JNS08178)
kEy WorDs aneurysm ischemia nimodipine
subarachnoidhemorrhage vasospasm
Abbreviations used in this paper: DIND = delayed ischemic neu-
rological deficit; DS = digital subtraction; GOS = Glasgow Outcome
Scale; ICU = intensive care unit; MCA = middle cerebral artery;
SAH = subarachnoid hemorrhage; SD = standard deviation; TCD =
transcranial Doppler.
J. Neurosurg. / Vol 110 / January, 2009
Intravenous or peroral nimodipine in subarachnoid hemorrhage
59
nimodipine intravenously. A major argument for a paren-
teral route has been the demonstration of more reliable and
stable plasma concentrations of nimodipine.
14,24,28
A direct
comparison between nimodipine administered perorally
and intravenously in regard to clinically meaningful differ-
ences has never been published.
In the present study, patients who had an SAH were
prospectively randomized to receive either peroral or in-
travenous treatment with nimodipine. We evaluated the
incidence of clinical signs of vasospasm in the acute phase
as well as the clinical and radiological outcome 3 months
after SAH.
Methods
The study was undertaken in the Department of Neu-
rosurgery, Lund University Hospital, which is the only
neurosurgical department in the southernmost part of Swe-
den, covering a population of 1.6 million. Patients were re-
cruited during a 30-month period between October 2002
and March 2005. Eligible for inclusion were patients with
aneurysmal SAH in whom randomization and nimodipine
treatment could be initiated within 48 hours after ictus. The
study was approved by the ethics committee at the Lund
University Medical Faculty and Medical Products Agency
in Sweden. Written informed consent was obtained from
either the patient or his or her next of kin.
The diagnosis of SAH was made using CT or lumbar
puncture if the CT failed to detect any blood. Clinical sta-
tus on admission was assessed using the Hunt and Hess
scale.
9
Blood distribution on CT was graded according
to the Fisher scale.
5
The presence of an intracranial an-
eurysm was confrmed with DS angiography within 24
hours after admission. Only patients with an angiographi-
cally verifed aneurysm qualifed for the study.
All patients were admitted to an ICU dedicated to neu-
rosurgical patients where the initial treatment and monitor-
ing was performed. Aneurysms were occluded using either
an exovascular (clipping) or endovascular technique (coil-
ing), usually within 48 hours of SAH. Tranexamic acid was
administered to prevent early rebleeding
8
prior to perma-
nent occlusion (1 g intravenously, every 6 hours).
Randomization and Treatment Protocol
Patients were randomized to receive either peroral or
intravenous nimodipine by drawing a sealed envelope. One
hundred slips with the text per os and 100 with iv infu-
sion were produced. All slips were put in identical enve-
lopes, which were sealed and then shuffed. After inclusion
into the study, an envelope was drawn for each consecutive
patient. Nimodipine was administered as 2 30-mg tablets
by mouth every 4 hours or as a continuous intravenous in-
fusion of 0.2 mg/ml at 10 ml/hour (Nimotop, Bayer AG).
If the patient became hypotensive (systolic blood pressure
< 110 mm Hg), a temporary reduction in the infusion rate
was allowed (typically to 5 ml/hour). Patients who were un-
able to swallow were given crushed tablets with water via a
nasogastric tube. Nimodipine treatment was continued for
at least 10 days. Treatment exceeded 10 days if the patient
showed signs of a DIND or increased fow velocities as
indicated by TCD ultrasonography (see below). Crossover
between treatment modalities was not allowed. The route
of administration could not be blinded to the clinician. If
a patient assigned to peroral treatment experienced signif-
cant gastric retention suggesting disturbed absorption of
nimodipine, he or she was withdrawn from the study.
Clinical Monitoring
Neurological status was monitored and documented
312 times every 24 hours, depending on clinical status.
Clinical deterioration with the onset of new focal neuro-
logical defcits or a diminished state of consciousness (de-
cline of > 1 point on the Glasgow Coma Scale) lasting for
at least 24 hours was interpreted as a DIND if other causes
such as hydrocephalus, rebleeding, or hyponatremia could
be excluded. Sedated patients on ventilator treatment were
assessed neurologically through the temporary discontinu-
ation of sedation. Measurements of blood fow velocities
in both MCAs according to TCD ultrasonography were
obtained on a daily basis. Blood fow velocities > 120
cm/second or increases of > 50 cm/second in 24 hours in
the MCA were interpreted as indicative of vasospasm.
1,29

Patients with a DIND or increased blood fow velocities
received, in addition to the nimodipine, hypervolemia-he-
modilution therapy. Induced hypertension was used very
rarely and thus was not recorded in the study. An external
ventricular drain was inserted in comatose patients and in
those with clinical deterioration due to hydrocephalus.
At 3 months after SAH, patients were assessed ac-
cording to the GOS.
10
At the same time, MR imaging was
performed to detect new areas of cerebral infarction. High-
signal lesions on T2-weighted or FLAIR MR sequences
were compared with hypodense areas on the original CT
scans. A neuroradiologist blinded to the treatment groups
performed the radiological evaluation.
Study End Points
The primary objective of this study was to determine
whether the mode of nimodipine administration (peroral
or intravenous) infuences the incidence of DINDs. Sec-
ondary end points were blood fow velocities in the MCAs
as measured by TCD ultrasonography, clinical outcome
based on the GOS, and new infarctions according to MR
imaging studies 3 months after SAH. We also analyzed
the need for hypervolemia-hemodilution therapy as well
as the time required in the ICU.
Statistical Analysis
Group comparisons were performed using the chi-
square test for proportions and the Student t-test for the
number of days with elevated TCD ultrasonography val-
ues and the number of days in the ICU. Probability values
< 0.05 (2-tailed) were considered statistically signifcant.
Results
Of 171 patients admitted to our center with a diagno-
sis of SAH, 106 were randomized in the study. Forty-nine
patients were randomized to the peroral group and 57 to
the intravenous group. The main reasons for not participat-
ing in the study were an inability to give informed consent
E. Kronvall et al.
60 J. Neurosurg. / Vol 110 / January, 2009
(early death and/or no relatives available), an angiogram
negative for aneurysm, and a late arrival to our unit (> 48
hours after ictus). During the study process repeated in-
terim analyses were performed, and based on the results
the inclusion process was interrupted after 106 patients.
One patient in the intravenous group was lost at follow-up.
Three patients in the peroral group were excluded due to
vomiting or gastrointestinal paralysis suggesting impaired
drug absorption. Clinical condition on admission did not
differ between the treatment groups, and neither did the
amount of bleeding on CT (Fisher grade) nor age distribu-
tion (Table 1). Sex distribution, type of aneurysm treatment
(open surgery or endovascular therapy), and number of pa-
tients with external ventricular drainage were also similar
in both groups. In contrast, aneurysm location differed be-
tween the 2 groups; there were more internal carotid artery
(ophthalmic, posterior communicating, anterior choroidal,
and internal carotid artery bifurcation) aneurysms as the
cause of SAH in the peroral group (chi-square = 8.50, p <
0.01) and more anterior cerebral artery (including anterior
communicating and pericallosal artery) aneurysms in the
intravenous group (chi-square = 5.23, p = 0.02). The pro-
portion of patients with bacterial ventriculitis did not differ
signifcantly between the groups.
There was no difference in the occurrence of DINDs
between treatment groups: 13 (28%) of 46 patients in the
peroral and 17 (30%) of 57 in the intravenous group (chi-
square = 0.03, p = 0.86; Table 2).
Measurements of blood fow velocity in the MCA
according to TCD ultrasonography were also similar in
both groups (Table 2). In 4 patients (2 in each group), re-
liable TCD ultrasonography examinations were not pos-
sible because of the cranial thickness. Twenty-two (50%)
of 44 patients in the peroral group and 25 (45%) of 55 in
the intravenous group had blood fow velocities > 120 cm/
second (chi-square = 0.20, p = 0.65). The average number
of days with blood fow velocities > 120 cm/second were
also similar: 2.3 3.1 (mean SD) in the peroral group
and 2.1 3.2 in the intravenous group (t = 0.19, p = 0.85).
Increases of > 50 cm/second in 24 hours were seen in
7 (16%) of 44 patients and 7 (13%) of 55 in the peroral
and intravenous groups, respectively (chi-square = 0.20, p
= 0.65). Histograms of the daily blood fow velocities in
both MCAs were strikingly similar (Fig. 1). The number
of patients treated with hemodilution and hypervolemia,
an indirect sign of vasospasm or impending vasospasm
as judged by the clinician, was similar in both groups (52
and 53%, chi-square = 0.00, p = 0.96). The mean time re-
quired in the ICU did not differ between the groups: 10.9
7.5 and 10.9 7.1 days in the peroral and intravenous
groups, respectively (t = 0.02, p = 1.00).
The distribution of clinical outcomes 3 months af-
ter SAH was similar in both groups (Table 3). None of
the patients ended up in a vegetative state (GOS Score 2).
Five patients in the peroral group and 8 in the intravenous
group died. The number of patients with a favorable clini-
cal outcome (GOS Score 4 or 5) did not differ between
therapeutic modalities: 35 (76%) of 46 in the peroral group
and 39 (70%) of 56 in the intravenous group (chi-square
= 0.53, p = 0.47). The number of patients with chronic
hydrocephalus requiring cerebrospinal fuid shunting was
also analyzed. In the peroral group, 12 (26%) of 46 pa-
tients received a shunt, as compared with 10 (19%) of 56
in the intravenous group (chi-square = 1.01, p = 0.31).
Magnetic resonance imaging follow-up was possible
in 33 patients in the peroral group and 41 in the intravenous
group 3 months after SAH. Reasons not to perform MR
imaging included death, claustrophobia, and pacemaker
implant. The number of patients with new infarctions did
not differ signifcantly between the groups: 14 (42%) of
33 patients in the peroral and 18 (44%) of 41 in the intra-
venous group (chi-square = 0.02, p = 0.90). An analysis
of only those who had clinical signs of vasospasmthat
is, either a DIND or pathological TCD ultrasonography
measurementsdid not reveal any signifcant differences
in the number of infarctions between treatment groups
(Table 4). In surviving patients in whom MR imaging was
contraindicated, a follow-up CT was performed. No differ-
ence in new infarctions (hypodense areas) was detected,
but the groups were too small for statistical analysis to be
meaningful.
TABLE 1: Summary of baseline data in 106 patients who
experienced SAH
No. of Patients (%)
Characteristic Peroral Intravenous
total no. of patients 49 57
mean age in yrs* 54 15 58 11
sex
female 38 (78) 43 (75)
male 11 (22) 14 (25)
admission Hunt & Hess grade
I 4 (8) 5 (9)
II 23 (47) 23 (40)
III 17 (35) 19 (33)
IV 2 (4) 8 (14)
V 3 (6) 2 (4)
Fisher grade
1 1 (2) 1 (2)
2 3 (6) 6 (11)
3 23 (47) 23 (40)
4 22 (45) 27 (47)
aneurysm location
anterior cerebral artery 15 (31) 30 (53)
MCA 8 (16) 13 (23)
internal carotid artery 19 (39) 8 (14)
vertebrobasilar artery 7 (14) 6 (11)
treatment
op 9 (18) 10 (18)
endovascular 39 (80) 47 (82)
none 1 (2) 0
external ventricular drainage 28 (57) 31 (54)
ventriculitis 10 (20) 7 (12)
* Values presented as the means SDs.
J. Neurosurg. / Vol 110 / January, 2009
Intravenous or peroral nimodipine in subarachnoid hemorrhage
61
Discussion
The present study was designed to investigate whether
the peroral administration of nimodipine is as effcient as
an intravenous route in preventing ischemic complications
following aneurysmal SAH. The comparison of peroral
and intravenous administrations revealed no differences in
the occurrence of DINDs, fow velocities in the MCA ac-
cording to TCD ultrasonography recordings, the need for
hypervolemia-hemodilution therapy, or the length of stay in
the ICU. In addition, there were no differences in clinical
outcome or number of new infarctions on imaging at the
3-month follow-up. The strikingly similar results for the 2
treatment modalities were consistent for all studied vari-
ables, which suggest that the fndings are reliable despite
the relatively small number of patients. The proportion of
patients that had a DIND (30%) or increased blood fow
velocities in the MCA (50%) is in agreement with values
in several previous studies.
3,6,12,17,25,27
A favorable clinical
outcome (GOS Score 4 or 5) in 7075% of patients is also
in keeping with data in the modern literature,
18,22,26
suggest-
ing that our study population is, in general, representative
of patients who have had an SAH. A control group without
nimodipine was not included in our study because to do
so could have been considered unethical and made patient
recruitment more diffcult.
The gold standard for diagnosing cerebral vasospasm
is DS angiography, which can detect vasospasm in up to
70% of patients who have had an SAH.
12
Thus, given its
potentially greater sensitivity, angiography might have
detected differences in effcacy between peroral and in-
travenous administrations in the present study. Nonethe-
less, because DS angiography carries a low risk of vascu-
lar complications (thromboembolism or dissection) and
because we do not routinely use angiography to detect
vasospasm in patients who have had an SAH, this imag-
ing method was not adopted in our study for practical and
ethical reasons. Note, however, that TCD ultrasonography
is a safe and noninvasive technique and has been shown
to correspond well with radiological fndings of cerebral
vasospasm.
15,23,29
A potential statistical bias in the study groups might
be the fact that 3 patients in the peroral group were ex-
cluded because of gastric retention and vomiting, prob-
ably causing inferior drug absorption. It is possible that
these patients were in worse clinical condition and there-
fore might have been more prone to vasospasm. Such bias
is diffcult to avoid with our study design, and it would
have been unethical not to offer such patients intrave-
TABLE 2: Signs of cerebral vasospasm
No./Total (%)
Parameter Peroral Intravenous
2
p Value
DIND 13/46 (28) 17/57 (30) 0.03 0.86
mean blood flow velocities in MCA
max >120 cm/sec 22/44 (50) 25/55 (45) 0.20 0.65
no. of days w/ >120 cm/sec 2.3 3.1* 2.1 3.2* 0.19 0.85
>50 cm/sec increase in 24 hrs 7/44 (16) 7/55 (13) 0.20 0.65
induced hemodilution/hypervolemia 24/46 (52) 30/57 (53) 0.00 0.96
* Values expressed as the means SDs.
Student t-test.
Fig. 1. Histogram demonstrating average blood flow velocities in
the MCA as measured with TCD ultrasonography (mean values of both
sides SD) plotted against time during the first 10 days after SAH. Flow
velocities slowly increase to peak on Day 8. Values for both groups are
almost identical. IV = intravenous group; PO = peroral group.
TABLE 3: Clinical outcome at the 3-month follow-up in 102
patients treated with nimodipine
No. of Patients (%)
Parameter Peroral Intravenous
total no. of patients 46 56
GOS score
5, good recovery 25 (54) 29 (52)
4, moderate disability 10 (22) 10 (18)
3, severe disability 6 (13) 9 (16)
2, vegetative state 0 0
1, death 5 (11) 8 (14)
4 or 5, favorable outcome* 35 (76) 39 (70)
*
2
= 0.53; p = 0.47.
E. Kronvall et al.
62 J. Neurosurg. / Vol 110 / January, 2009
nous treatment (thus leading to exclusion from the study
as crossover was not allowed). A power analysis was not
conducted when designing the study given that our pur-
pose was to determine whether peroral and intravenous
nimodipine treatment had similar effcacy in preventing
cerebral ischemia and not primarily to detect any actual
differences. Instead, repeated interim analyses were per-
formed to determine the size of the study.
As in previous randomized studies on the clinical ef-
fcacy of nimodipine,
3,19
neither plasma nor cerebrospinal
fuid concentrations were measured. Although the phar-
macokinetics of intravenous nimodipine have been thor-
oughly investigated,
14
relatively little is known concerning
the pharmacokinetics of peroral nimodipine.
24,28
Vinge and
colleagues
28
have demonstrated considerable variations in
nimodipine concentrations after peroral administration
(range < 396 ng/ml, average 13.2 ng/ml prior to next oral
dose at 45 mg every 4 hours) as compared with those after
intravenous delivery when levels were more stable (range
1558 ng/ml, average 27 ng/ml at 2 mg/hour). The large
variations in plasma concentration with oral treatment
probably refect variability in frst-pass elimination.
28
In
a pilot study by Soppi et al.,
24
plasma concentrations of
nimodipine varied substantially after peroral administra-
tion (area under the curve, range 0.121 g min/ml) as
compared with intravenous administration (range 218
g min/ml). In addition, the absorption of peroral ni-
modipine was affected in patients with a decreased level
of consciousness, and concomitant phenytoin medication
may reduce its bioavailability via enzyme induction (cy-
tochrome P450) in the liver. Other studies have shown a
relationship between intravenous dosing of nimodipine and
blood fow velocities in the MCA as measured with TCD
ultrasonography.
23,30
These data suggest that intravenous
administration is more reliable in terms of providing op-
timal bioavailability of nimodipine for the patient. In fact,
parenteral administration of nimodipine is the preferred
treatment in several centers (particularly in Europe, per-
sonal communications) for these reasons. However, results
of the present study suggest that such variation in plasma
nimodipine concentrations has no signifcant clinical rele-
vance. Because intravenous administration is considerably
more expensive (in Sweden ~ 25-fold), carries a higher risk
of induced hypotension,
7,20
and requires invasive central
venous access, our results strongly suggest that nimodipine
should be administered via the oral route unless disturbed
absorption or metabolism is suspected.
Conclusions
In summary, previous studies have demonstrated that
calcium antagonists reduce the risk of poor outcome and
secondary ischemia after aneurysmal SAH.
2,3
Although
the peroral and intravenous routes should have similar
benefcial effects, benefts have been proven in clinical
trials only for peroral administration.
3
Results in the pres-
ent study show that the effcacy of the peroral and intrave-
nous administration of nimodipine is similar from a prac-
tical clinical point of view. Thus, the incidence of DINDs,
TCD ultrasonography measurements, clinical outcomes,
and number of infarctions on MR imaging were the same
for both types of administration. Because peroral treat-
ment is safer and considerably less expensive, we suggest
that parenteral nimodipine treatment be restricted to pa-
tients with derangement in enteral absorption or metabo-
lism.
Disclaimer
The authors report no conflict of interest concerning the mate-
rials or methods used in this study or the findings specified in this
paper.
Acknowledgments
We thank Susanne Mnsson for assistance in the collection of
data, and Lennart Brandt, M.D., Ph.D., for valuable discussions.
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Manuscript submitted March 24, 2008.
Accepted July 2, 2008.
Please include this information when citing this paper: pub-
lished online October 10, 2008; DOI: 10.3171/2008.7.JNS08178.
Address correspondence to: Erik Kronvall, M.D., Department of
Neurosurgery, Lund University Hospital, S-221 85 Lund, Sweden.
email: erik.kronvall@med.lu.se.