Full text of DOI:10.1007/BF03019868

1196
REPORTS OF INVESTIGATION
Continuous nicardipine
infusion to control
blood pressure after
evacuation of acute
cerebral hemorrhage
Tomoki Nishiyama MD PhD,*
Takeshi Yokoyama DDS PhD,†
Takashi Matsukawa MD PhD,‡
Kazuo Hanaoka MD PhD,§
Purpose: To explore the long-term effects of the calcium antagonist, nicardipine, on cerebral hemodynamics in
patients with acute cerebral hemorrhage, we investigated the effects of nicardipine infusion on intracranial pres-
sure (ICP), middle cerebral arterial blood flow velocity (Vmca) , and computed tomographical (CT) findings of
bleeding and edema.
Methods: Twenty-two patients with acute cerebral hemorrhage were infused with nicardipine for > 72 hr to
decrease blood pressure. Blood pressure, heart rate, conscious level, Vmca, pulsatility index (PI, using transcra-
nial Doppler), ICP, cerebral perfusion pressure (CPP) and platelet counts were monitored. CT examination was
also performed to detect the changes of bleeding (hematoma) and/or brain edema.
Results: Blood pressure decreased (20 to 30% from control, P < 0.05) without any changes in heart rate.
Platelet count did not change neither did Vmca and PI change on either the intact or injured side. The ICP
decreased 24 hr after the end of infusion from 30 ± 12 mmHg to 20 ± 9 mmHg (P = 0.036) but was still high-
er than normal. The CPP decreased at 24 hr (75 ± 14 mmHg, P = 0.026) and 72 hr (73 ± 15 mmHg, P =
0.024) from the baseline (99 ± 17 mmHg). Conscious level improved but not significantly and CT findings did
not show any exacerbation in bleeding or edema .
Conclusion: In patients with acute cerebral hemorrhage, nicardipine infusion to decrease blood pressure by 20
to 30% had no effect on Vmca, ICP, cerebral bleeding and edema, but decreased CPP.
Objectif : C’est afin d’explorer les effets à long terme de l’inhibiteur calcique, nicardipine, sur l’hémodynamie
cérébrale de patients victimes d’hémorragie cérébrale aiguë, que nous avons examiné les effets d’une perfusion
de nicardipine sur la pression intracrânienne (PIC), la vitesse circulatoire de l’artère cérébrale moyenne (Vacm) et
la scanographie du saignement et de l’œdème.
Méthode : Vingt-deux patients souffrant d’hémorragie cérébrale aiguë, ont reçu une perfusion de nicardipine
pendant > 72 h, pour diminuer la tension artérielle. La tension artérielle, la fréquence cardiaque, le niveau de
conscience, la Vacm, l’indice de pulsatilité (IP, au moyen du Doppler transcrânien), la PIC, la pression de perfusion
cérébrale (PPC) et la numération plaquettaire ont été surveillés. La scanographie a été aussi réalisée dans le but
de détecter des modifications du saignement (hématome) et/ou de l’œdème cérébral.
Résultats : La tension artérielle a baissé (de 20 à 30 % des mesures témoins, P < 0,05), mais la fréquence car-
diaque, la numération plaquettaire et la Vacm n’ont pas été modifiées. La PI a changé du côté intact et du côté lésé.
La PIC a diminué 24 h après la fin de la perfusion, passant de 30± 12 mmHg à 20 ± 9 mmHg (P = 0,036), mais
est demeurée plus élevée que la normale. La PPC a baissé à 24 h (75 ± 14 mmHg, P = 0,026) et à 72 h (73 ±
15 mmHg, P = 0,024), comparée à la PPC de base (99 ± 17 mmHg). Le niveau de conscience s’est amélioré,
mais non de façon significative et la scanographie n’a pas montré d’exacerbation du saignement ou de l’œdème.
Conclusion : Chez les patients victimes d’hémorragie cérébrale aiguë, une perfusion de nicardipine, utilisée
pour diminuer la tension artérielle de 20 à 30 %, n’a pas d’effet sur la Vacm, la PIC, le saignement ou l’œdème
cérébral, mais diminue la PPC.
From the Department of Surgical Center, The Institute of Medical Science,* The University of Tokyo, Tokyo, the Department of
Anesthesiology and Resuscitology, Kochi Medical School,† Kochi, the Department of Anesthesia, Yamanashi Medical University,‡
Yamanashi, and the Department of Anesthesiology, The University of Tokyo,§ Tokyo, Japan.
Address correspondence to: Tomoki Nishiyama MD PhD. 3-2-6-603, Kawaguchi, Kawaguchi-shi, Saitama, 332- 0015, Japan. Phone: 81-
3-5449-5356; Fax: 81-3-5449-5356; E-mail: nishiyam@ims.u-tokyo.ac.jp
Accepted for publication September 5, 2000.
CAN J ANESTH 2000 / 47: 12 / pp 1196–1201

Nishiyama et al.: ACUTE CEREBRAL HEMORRHAGE
1197
ORpatients with acute cerebral hemorrhage,
immediate hypotensive therapy is often nec-
essary and calcium antagonists have been
velocity - end diastolic velocity) / (mean velocity). The
ICP was monitored continuously using a sensor insert-
ed upon brain parenchyma at surgery and cerebral per-
fusion pressure (CPP) was calculated as mean blood
pressure - ICP.
Data are expressed as mean standard deviation.
Statistical analysis was performed with one-way
repeated measures analysis of variance (ANOVA) fol-
lowed by paired t test for blood pressure, heart rate
and ICP. For Vmca and PI, two-way repeated mea-
sures ANOVA followed by the contrast was used. The
changes of JCS and CT findings were analyzed with
Friedman test. A P value < 0.05 was considered statis-
tically significant.
F
used for this purpose. However, there is con-
troversy whether calcium antagonists can be used safe-
ly in patients with acute cerebral hemorrhage because
of the risk of increased bleeding1 and intracranial pres-
sure.2 In this study, we explored the safety of hypoten-
sive therapy with the calcium antagonist, nicardipine,
in patients with acute cerebral hemorrhage in terms of
intracranial pressure (ICP), cerebral blood flow veloc-
ity, and computed tomographical (CT) findings of
bleeding and edema.
Methods
After the approval of our institutional research commit-
tee and informed consent from the patient’s family, 22
patients with acute cerebral (putaminal) hemorrhage
secondary to hypertension who underwent surgical
drainage of the hematoma were studied. Those with
liver or renal damage were excluded. The patients, 14
male and 8 female, were 64 15 (range: 4779) yr old.
After surgery under general anesthesia the tracheas were
Results
The infusion dose of nicardipine was 1.14 0.45 (range:
0.61~1.69) µg·kg– 1·min– 1 at 24 hr and 0.60
0.45
(0.24~1.06) µg·kg– 1·min– 1 at 72 hr after the start of infu-
sion. In total 484 343 (138~826) mg of nicardipine
was administered for 213 114 (92~323) hr.
Blood pressure decreased during and 24 hr after the
end of the nicardipine infusion but heart rate did not
extubated within 24 hr. The PaCO was controlled
change during the study (Figure 1). The PaCO after
2
2
between 30 and 35 mmHg during ventilation.
extubation was 34 6 mmHg, which was not different
from that during ventilation (32 3 mmHg).
After surgery, an infusion of nicardipine was started
at 1 µg·kg–1·min–1 and the rate was adjusted to keep sys-
tolic blood pressure between 120 mmHg and 160
mmHg (20 to 30% reduction compared with the pre-
nicardipine value) indicated by neurosurgeons.
Nicardipine infusion was continued for more than 72
hr. Concentrated glycerin fructose solution (Glyceol™,
osmolarity is seven times of lactated Ringer’s solution,
Ootsuka, Osaka, Japan), 400-600 mL (divided doses
twice to three times a day), 250 mg phenytoin (divided
dose twice a day) per day, and antibiotics were adminis-
tered in all cases. Blood pressure (directly measured
through a catheter in the radial artery), heart rate, con-
sciousness level, middle cerebral arterial blood flow
velocity (Vmca), pulsatility index (PI), ICP and platelet
counts were monitored before, 24 and 72 hr after the
start of nicardipine infusion and 24 hr after the end of
nicardipine infusion. Computed tomographic (CT)
examination was performed before, 24 and 72 hr after
the start of nicardipine infusion and 24 hr after the end
of nicardipine infusion to detect the changes of bleed-
ing (hematoma) and/or brain edema, which was diag-
nosed by the neurosurgeons. Consciousness was
monitored using Japan Coma Scale (JCS, see
Appendix). The Vmca was measured and PI was calcu-
lated by Transcranial Doppler ultrasound flowmetry
(TC2-64™; EME, Überlingen, Germany). PI was cal-
culated using the following formula: PI = (peak systolic
– 3
Platelet counts were 12.6 5.2 ·mm , 10.6 6.9
–3
– 3
·mm–3, 10.4
7.2 ·mm , and 11.1
5.7 ·mm
before and at 24 hr and 72 hr after the start of infu-
sion, and 24 hr after the end of infusion, respectively
(P: NS). Hematocrit was 29 4%, 28 5%, 31 4%,
and 32 3% before infusion, at 24 hr and 72 hr after
the start of infusion, and 24 hr after the end of infu-
sion, respectively (P: NS).
The Vmca and PI did not change in either the
intact or injured side during the study (Figure 2).
There were no differences between the intact and
injured sides. Intracranial presure decreased 24 hr
after the end of the infusion but was still higher than
normal (Figure 3): CPP decreased at 24 and 72 hr but
was > 50 mmHg (Figure 3). Consciousness levels
(shown as JCS) did not change (Table I) and CT find-
ings did not show any exacerbation of bleeding and
edema (Table II).
Discussion
The present study showed that continuous infusion of
nicardipine to decrease blood pressure in patients after
evacuation of acute cerebral hemorrhage did not affect
Vmca and ICP, but decreased CPP. It did not exacer-
bate bleeding, edema, or neurological outcome.
Another calcium antagonist, nimodipine, increased
surgical bleeding in cardiac surgery.1 The reason for

1198
CANADIAN JOURNAL OF ANESTHESIA
FIGURE 2 Mean cerebral blood flow velocity of middle cerebral
artery (upper) and pulsatility index (lower) are shown. Total num-
ber of the patients were 22. Bars indicate standard deviation.
Closed circles are intact side and open circles are injured side. No
significant differences are seen between intact and injured side.
FIGURE 1 Blood pressure and heart rate
Blood pressure (upper; closed circle: systolic, open circle: diastolic)
and heart rate (lower) are shown. Total number of the patients
were 22. Bars indicate standard deviation. *: P < 0.05 vs the con-
trol value (Before infusion).
study, we measured only platelet count and not
platelet function. However, CT findings showed no
increase in bleeding or hematoma. Therefore, even if
nicardipine has antiplatelet function, it did not exacer-
bate cerebral bleeding in patients after evacuation of
acute cerebral hemorrhage.
this increased bleeding was suggested to be due to
vasodilatation and/or due to the antiplatelet action of
nimodipine.1 In contrast, oral nimodipine has minimal
antiplatelet activity.3 The calcium antagonist nifedip-
ine reduced platelet aggregation and prolonged bleed-
ing time after a single oral dose of 20 mg.4 Nicardipine
might also attenuate platelet secretion.5 In the present
In anesthetized dogs, nicardipine increased ICP
and cerebral blood flow.2 Nicardipine also increased

Nishiyama et al.: ACUTE CEREBRAL HEMORRHAGE
1199
TABLE I Consciousness
Consciousness
(JCS)
Before infusion 24 hr 72 hr 24 hr after the
end of infusion
300
200
100
30
20
10
3
2
1
0
0
1
1
3
6
7
2
1
1
0
0
0
0
4
6
7
3
1
1
0
0
0
0
2
4
5
4
3
2
2
0
0
0
1
3
4
4
3
4
3
The number of patients is shown.
JCS: Japan Coma Scale (See Appendix)
TABLE II CT findings
24 hr
72 hr 24 hr after the
end of infusion
Hemorrhage Increase
(Hematoma) No change
Decrease
0
4
18
0
0
3
19
0
0
1
21
0
Edema
Increase
No change
Decrease
10
12
8
14
5
17
The number of patients is shown.
Increase, No change, and Decrease: compared to the findings
before nicardipine infusion judged by neurosurgeons who did not
know of this study.
Edema was diagnosed by the changes of sulcus and ventricle.
which could decrease ICP. In addition, ICP was
recorded only at three times after nicardipine infusion
with the first at 24 hr after the start of the infusion. It
is possible that the initial increase in ICP was missed
The third suggested reason of the absence of increased
ICP in the present study might be that the ICP would
have decreased if nicardipine had not been used
because ICP remained higher than normal despite the
use of hyperventilation and an osmotic diuretic. In the
present study, the reduction in ICP appeared to follow
the reduction in blood pressure. This would suggest
that cerebral autoregulation was impaired and may
explain why an increase in ICP was not observed with
nicardipine infusion. However, CPP was > 50 mmHg
during nicardipine induced hypotension. Therefore, in
patients with cerebral hemorrhage to whom osmotic
diuretics such as concentrated glycerinfructose solu-
tion may be administered, nicardipine infusion nay be
used safely without increasing ICP or decreasing CPP
to a critical level.
FIGURE 3 Intracranial pressure (ICP, upper) and cerebral per-
fusion pressure (CPP, lower) are shown. Total number of the
patients were 22. Bars indicate standard deviation. *: P < 0.05 vs
the control value (Before infusion).
ICP in patients with6 or without7 intracranial hyper-
tension. This increase was associated with decreases in
arterial blood pressure and CPP.7 The present results
showed no increase in ICP, but CPP decreased. The
direct effect of nicardipine on ICP can not be deter-
mined from the present study because of the adminis-
tration of concentrated glycerin fructose solution,

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CANADIAN JOURNAL OF ANESTHESIA
Hyperventilation attenuated the increase of ICP by
Acknowledgement
We would like to thank Professor Chingmuh Lee MD
Department of Anesthesiology, University of California
Los Angeles for his useful comments on this study.
nicardipine in anesthetized dogs.8 In the present
study, all patients were slightly hyperventilated and
this may explain why ICP did not increase in contrast
to other studies.2,7
,
Nicardipine increased local cerebral blood flow and
internal carotid blood flow velocity under isoflurane
anesthesia.9 Topically administered nicardipine to
cerebral vessels dilated small arterial cortical vessels
and increased cerebral oxygen tension in patients
undergoing surgery for extra-intracranial anastomo-
sis.1 0 However, in another study, local cerebral blood
flow did not change during nicardipine infusion, but
blood flow velocity increased after nicardipine infu-
sion.11 The present results showed no changes of
Vmca and PI while systemic blood pressure was
decreased by nicardipine infusion. A lack of change in
PI indicates that the resistance of the middle cerebral
artery did not change.1 2 Absence of changes in Vmca
and PI and the lack of difference in hematocrit suggest
that blood flow did not change. Therefore, it is sug-
gested that in the patients with acute cerebral hemor-
rhage, nicardipine infusion to decrease blood pressure
about 25% does not affect cerebral blood flow.
There are no reports of the pharmacokinetics of
continuous infusion of nicardipine. Nicardipine is
metabolized in the liver and the metabolite had little
vasodilating effect. Liver damage but not renal dam-
age might prolong or enhance the effects of nicardip-
ine. However, no patients in the present study had
liver damage. Therefore, the dose used might be
decreased for the patients with liver damage.
Sympathetic activity was increased by nicardipine
infusion and it gradually decreased after three days of
the start of infusion.1 3 The rein-angiotensin-aldos-
terone system was also activated during nicardipine
infusion.1 4 These changes might have some roles in
vasodilatation, ICP, and/or cerebral blood flow.
Nitroglycerin increased mean cerebral blood flow
measured by SPECT on the bleeding side but not on
the intact side while systemic blood pressure
decreased.1 5 We could not find any reports of differ-
ences in the effects of nicardipine on cerebral blood
flow between the bleeding and intact sides. Our pre-
sent study suggested that nicardipine did not induce
different effects on cerebral blood flow in the injured
and intact sides.
References
1 Wagenknecht LE, Furberg CD, Hammon JW, Legault C,
Troost BT. Surgical bleeding: unexpected effect of a cal-
cium antagonist. BMJ 1995; 310: 776–7.
2 Takenaka T, Handa J. Cerebrovascular effects of YC-
93, a new vasodilator, in dogs, monkeys and human
patients. International Journal of Clinical
Pharmacacology and Biopharmacy 1979; 17: 1–11.
3 Feinberg WM, Bruck DC. Effect of oral nimodipine on
platelet function. Stroke 1993; 24: 10–3.
4 Dale J, Landmark KH, Myhre E. The effects of nifedip-
ine, a calcium antagonist, on platelet function. Am
Heart J 1983; 105: 103–5.
5 Wigley FM, Wise RA, Malamet R, Scott TE. Nicardipine
in the treatment of Raynauds phenomenon.
Dissociation of platelet activation from vasospasm.
Arthritis Rheum 1987; 30: 281–6.
6 Hirayama T, Katayama Y, Kano T, Tsubokawa T.
Control of systemic hypertension with diltiazem, a cal-
cium-antagonist, in patients with a mildly elevated
intracranial pressure: a comparative study. Neurol Res
1994; 16: 97–9.
7 Nishikawa T, Omote K, Namiki A, Takahashi T. The
effects of nicardipine on cerebrospinal fluid pressure in
humans. Anesth Analg 1986; 65: 507–10.
8 Nishikawa T, Namiki A, Omote K. The effects of arter-
ial carbon dioxide tension upon increase in cere-
brospinal fluid pressure induced by nicardipine.
(Japanese) Masui 1988; 37: 176–9.
9 Abe K, Iwanaga H, Inada E. Effect of nicardipine and
diltiazem on internal carotid artery blood flow velocity
and local cerebral blood flow during cerebral aneurysm
surgery for subarachnoid hemorrhage. J Clin Anesth
1994; 6: 99–105.
10 Gaab MR, Czech T, Korn A. Intracranial effects of
nicardipine. Br J Clin Pharmacol 1985; 20: 67S–74.
11 Abe K, Demizu A, Imanishi M, Iwanaga H. The effect of
nicardipine on internal carotid artery blood flow velocity,
local cerebral blood flow and carbon dioxide reactivity.
(Japanese) No Shinkei Geka 1993; 21: 1097–101.
12 Gosling RG, Dunbar G, King DH, et al. The quantita-
tive analysis of occlusive peripheral arterial disease by a
noninvasive ultrasound technique. Angiology 1971;
22: 52–5.
In conclusion, for patients with acute cerebral hem-
orrhage, nicardipine infusion to decrease blood pres-
sure by 20 to 30% has no effects on Vmca, ICP,
cerebral bleeding and edema, but decreases CPP.
13 Nishiyama T, Hirasaki A, Odaka Y, Araki J, Seto K,
Goto I. Changes of sympathetic tone during long-term
nicardipine infusion. (Japanese) Circulation Control
1991; 12: 435–40.

Nishiyama et al.: ACUTE CEREBRAL HEMORRHAGE
1201
14 Nishiyama T, Toda N. Effects of long-term nicardipine
infusion on renin-angiotensin-aldosterone system.
(Japanese) Jpn J Intensive Care Med 1994; 18: 987–92.
15 Hojo A, Nakagawara J, Takeda R, Sasaki O,
Nakamura J, Suematsu K. Effect of nitroglycerin on sys-
temic blood pressure and cerebral blood flow in patients
with acute hypertensive hemorrhage. (Japanese) Jpn J
Intensive Care Med 1993; 17: 1101–9.
Appendix
Japan Coma Scale (3-3-9)
III.Deep coma, coma, or semi coma with noxious
stimuli
300: No response to pain
200: Withdrawal response to pain
100: Localizing to pain
II. Lethargy, hypersomnia, somnolence, or drowsi-
ness without verbal stimuli
30: Eye-opening by repeated verbal stimuli
20: Obeying to easy command
10: Purposeful movement and speech but a lot
of mistakes
I. Awakening without any stimuli
3: Can not tell own name and birth date
2: Disoriented
1: Not so clear
0: Clear