what we learn from the newest

evidence ?
Paulus Sugianto
Neurology Dept, Dr. Soetomo Hospital/
Faculty of Medicine, Airlangga University,
Surabaya
 Stroke is the leading cause of Death among Indonesians, accounts for
15.4% of all cause deaths in Indonesian, with age-gender-
standardized death rate 99/100,000 and age-gender-standardized
disability rate 685/100,000.
Stroke prevalence is 0.0017 % in rural Indonesia and 0.022% in urban
Indonesia
The mean age of stroke patients is 58.8 years.
Currently, there are only 40 stroke units in Indonesia, and all located
in city hospitals which have neurology, neurosurgery, neuroimaging
and rehabilitative services

2
 1,4%

18,5% Sub Arachnoid

haemorrhage
Intra Cerebral
42,9% Haemorrhage
Ischaemic Stroke
Stroke Prevalence in Indoneisa :
8,2 1.

1. Ministry of Health. Riset Kesehatan Dasar (RISKESDAS). Indonesia: Ministry of Health: 2007.
2. Misbach J, Ali W. Stroke in Indonesia: a first large
3 prospective hospital-based study of acute
stroke in 28 hospitals in Indonesia. J Clin Neurosci 2001; 8:245-9
 Stroke is the first leading cause of
disability
Stroke is the third leading cause of death

67% of stroke is ischemic type

4
No. Underlying Disease Hemorrhagic stroke Ischemic Stroke
1 Previous Stroke 29,4 35,8
2 Transient Ischemic Attack 3,1 4,4
3 Peripheral Arterial Disease 1,0 1,2
4 Hypertension 71,9 63,8
5 Dyslipidemia 10,2 15,1
6 Diabetes Mellitus 11,2 24,5
7 Atrial Fibrilation 1,3 3,2
8 Angina Pektoris 1,1 2,1
9 Infarct Miokard 1,9 2,8
10 Heart valve disorder 0,3 0,8
11 Heart failure 2,0 3,0
12 On Antithrombolytic agent 2,2 5,1
13 Anemia 1,5 1,9
Stroke Registri 2012-2013
RISK FACTORS HEMORRHAGIC STROKE
0,3 Stroke based on
Underlying Disease and Stroke type.
1,9
1,1 2 2,2 1,5 Stroke sebelumnya
1,3
11,2 29,4 TIA
10,2 3,1
1 Peripheral Arterial
Disease
Hypertension Hipertensi

Dislipidemia
71,9
Diabetes Mellitus

7 Stroke Registri 2012-2013

CVA Infark CVA Infark + rtPA CVA bleeding

8
 Infarct
Type of Blood Pressure
Stroke
should be
AHA-ASA reduced if ~
Guideline EUSI
Type of ICH guidelines
Stroke SAH
Blood Pressure
should be
AHA-ASA
Guideline EUSI
controlled early
9
Which one for which condition?
 Classification Calcium Antagonists
Generation:
First Second Third Latest
Verapamil Felodipine Amlodipine Lercanidipine
Nifedipine Isradipine (hydrophilic) (lipophilic)
Diltiazem Nicardipine
Nimodipine
Nisoldipine
Nitrendipine
Prototype Tissue selectivity Tissue selectivity Tissue selectivity
gradual onset gradual onset
Plasma controlled membrane controlled
J Clin Basic Cardiol 1999;2:155
Calcium Channel Blockers ( CCBs )

Dihydropyridine ( DHP )
Nifedipine, Felodipine, Nicardipin,
Amlodipine
Non-Dihydropyridine ( NDHP )
Diltiazem, Verapamil
 Nicardipine Diltiazem
(dihydropyridine) (benzothiazepine)
Peripheral
Vasodilation1
+++++ +++
Coronary
Vasodilation2
+++++ +++
Suppression
of SA Node2 + +++++
Suppression
of AV Node2 0 ++++
Suppression
of Cardiac Contractility2 0 ++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547.

2. Adapted from Goodman and Gilmans: The Pharmacologic Basis of Therapeutics. 9th ed. 2001.
 NICARDIPINE and DILTIAZEM

NICARDIPINE DILTIAZEM

Target organ Arteriole (ca Channel) Arteriole (ca Channel)

Clinical effect Vasodilatation : BP Vasodilatation : BP

decreased decreased
Heart Rate
* Diltiazem and Nicardipine on HR of
Hypertensive emergency
Heart Rate (beat/minute)
patients
< 60 60 - 80 > 80

Nicardivine I.V. Diltiazem I.V

Blood Pressure lowering using Nicardipine in
Patients with ICH : Samurai Study

*Samurai Study
17 J Hypertens. 2012 Dec;30(12):2357-64.
 Samurai
Study

18
19
20
21
22
 General Management of
Hypertensive Emergency
Patients should be admitted to an ICU for continuous
monitoring of BP and parenteral administration of an
appropriate agent1
The initial goal therapy is to reduce mean arterial BP by
no more than 25% (within minutes to 8 hour) 2.
Patient is receiving IV or IA fibrinolysis, the goal BP is an
SBP < 185 mm Hg and DBP < 110 mm Hg. After treatment
with fibrinolysis, the SBP should be maintained < 180 mm
Hg and the DBP at < 105 mm 23Hg for 24 hours 1,2
Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 2560-70
1
2
25
Decreasing Blood Pressure in
Certain Conditions
1. Acute ischemic stroke *):
SBP >220 ; DBP > 120.
2. rtPA candidate **):
SBP >185 ; DBP > 110 (Class I; Level of Evidence B) and maintained
below 180/105 for at least the first 24 hours after iv rtPA treatment
3. Acute hemorrhage stroke :
SBP > 180 ; DBP > 100 or MAP >145
4. Acute Stroke with hypertension : * ASA Guideline, May
Hypertensive encephalopathy
26
2007 : Class I, Level of
Aortic dissection evidence C.
 Candidates
Patient for Acute
otherwise eligible Reperfusion
for acute Therapy
reperfusion therapy
except that BP is >185/110 mm Hg:
Labetalol 1020 mg IV over 12 minutes, may repeat 1 time;
or
Nicardipine 5 mg/h IV, titrate up by 2.5 mg/h every 515
minutes, maximum 15 mg/h; when desired BP reached,
adjust to maintain proper BP limits; or
Other agents (hydralazine, enalaprilat, etc) may be
considered when appropriate
If BP is not maintained at or below
27
185/110 (AHA/ASA
mm Hg,: Stroke
do not 2013)
 Candidates for Acute Reperfusion Therapy
Management of BP during and after rtPA or other acute
reperfusion therapy to maintain BP at or below 180/105 mm Hg:
Monitor BP :
every 15 minutes for 2 hours from the start of rtPA therapy, then
every 30 minutes for 6 hours, and then
every hour for 16 hours
If systolic BP >180230 mm Hg or diastolic BP >105120 mm Hg
Use IV preparation
If BP not controlled or diastolic BP >140 mm Hg, consider IV
28
sodium nitroprusside: (AHA/ASA : Stroke 2013)
29
30
 Rehemorrhage in ICH

BP
should be
controlled
early
6 hrs later

Initial
31
Current suggested recommendations for target BP
1. If SBP is >200 mm Hg or MAP is >150 mm Hg, then consider
aggressive reduction of BP with continuous intravenous
infusion, with frequent BP monitoring every 5 min.
2. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is
the possibility of elevated ICP, then consider monitoring
ICP and reducing BP using intermittent or continuous
intravenous medications while maintaining a cerebral
perfusion pressure >60 mm Hg.
3. If SBP is 180 mm Hg or MAP is 130 mm Hg and there is note
evidence of elevated ICP, then consider a modest reduction
of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg)
using intermittent or continuous intravenous medications
to control BP and clinically reexamine
32 the patient every 15
min. (Stroke 2010;41:2108-2129)
4. In patients presenting with a systolic BP of 150 to 220
mm Hg, acute lowering of systolic BP to140 mm Hg is
probably safe (Class IIa; Level of Evidence: B). (New
recommendation)

33
(Stroke 2010;41:2108-2129)
(Stroke. 2015;46:000-000. DOI: 10.1161/STR.0000000000000069.)

34
Current recommendations for target BP :
For ICH patients presenting with SBP between 150-220
mm Hg and without contraindication to acute BP
treatment, acute lowering of SBP to 140 mm Hg is safe
(Class I; Level of Evidence A) and can be effective for
improving functional outcome (Class IIa; Level of
Evidence B). (Revised from the previous guideline)
BP should be controlled in all ICH patients (Class I;
Level of Evidence A). (Revised from the previous
guideline)
Measures to control BP should begin immediately after
ICH onset (Class I; Level of 35
Evidence A). (New
recommendation) A long-term goal of(Stroke 2010;41:2108-2129)
BP <130 mm Hg
Summary
To recent consensus, decreasing BP in acute
ischemic stroke is recommended if systolic >
220 mmHg or diastolic > 120 mmHg.
Patient otherwise eligible for acute reperfusion
therapy except that BP is >185/110 mm Hg
To recent consensus, decreasing BP in acute
haemorrhagic stroke is recommended.
Choose parenteral antihypertensive drugs and
do the BP control cautiously36

Nicardipine has been demonstrated to be one

38
39
40
41
42
43
44
 General Management of
Hypertensive Emergency
Patients should be admitted to an ICU for continuous
monitoring of BP and parenteral administration of an
appropriate agent1
The initial goal therapy is to reduce mean arterial BP by
no more than 25% (within minutes to 8 hour) 2.
Patient is receiving IV or IA fibrinolysis, the goal BP is an
SBP < 185 mm Hg and DBP < 110 mm Hg. After treatment
with fibrinolysis, the SBP should be maintained < 180 mm
Hg and the DBP at < 105 mm 45Hg for 24 hours 1,2
Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 2560-70
1
2
General Management of
Hypertensive Emergency (contd)
If this level of BP is well tolerated and the
patients is clinically stable , further
gradual reductions toward a normal BP can
be implemented in the next 24 to 48 hours.
Exceptions :
o Ischemic stroke
o Aortic dissection SBP should < 100 mmHg
46
o Patients whom BP is lowered
Chobanian to
AV et al, The JNC 7 enable
report, the2560-70
JAMA 2003;389:
Blood Pressure reduction target of
crisis hypertensive patients:
* Parenteral anti hypertension is given
based on the procedure of crisis
hypertensive treatment with MAP
reduction 20-25% from the baseline in the
first hour.
Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008)
B. Diltiazem (Herbesser) IV (50 mg/ampul)
* Diltiazem 10mg IV given by bolus in 1-3 menit
followed by drip infusion 50 mg/jam in 20 menit.
* When the BP reduction achieve at >20% from the
baseline, the dosage is adjusted to 30 mg/jam until
the BP reduction target achieved.
* Followed by maintenance dosage 5-10 mg/jam,
observed in 4 hours, if stabil switch to oral.
* Precaution to the patients with AV Block and Heart
Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008)
 * Drugs used in the treatment of emergency
hypertension (InaSH 2008, CHEST 2007)
* Clonidin (Catapres) IV (150 mcg/ampul)
* Diltiazem (Herbesser IV); 50 mg/ampul
Nicardipin (Perdipin IV (2 mg dan 10 mg/ampul)
Labetalol (Normodyne) IV*
Nitroprusside (Nitropress, Nipride) lV
Nitroprusside in drip infus with dosage dosis
0.25-10.00 mcg/kg/menit
Nitogliserin (nitrat)
Chest 2007;131;1949-1962
Konsensus Penanggulangan Krisis Hipertensi (InaSH 2008)
50
Current suggested recommendations for target BP
1. If SBP is >200 mm Hg or MAP is >150 mm Hg, then consider
aggressive reduction of BP with continuous intravenous
infusion, with frequent BP monitoring every 5 min.
2. If SBP is >180 mm Hg or MAP is >130 mm Hg and there is
the possibility of elevated ICP, then consider monitoring
ICP and reducing BP using intermittent or continuous
intravenous medications while maintaining a cerebral
perfusion pressure >60 mm Hg.
3. If SBP is 180 mm Hg or MAP is 130 mm Hg and there is note
evidence of elevated ICP, then consider a modest reduction
of BP (eg, MAP of 110 mm Hg or target BP of 160/90 mm Hg)
using intermittent or continuous intravenous medications
to control BP and clinically reexamine
51 the patient every 15
min. (Stroke 2010;41:2108-2129)
4. In patients presenting with a systolic BP of 150 to 220
mm Hg, acute lowering of systolic BP to140 mm Hg is
probably safe (Class IIa; Level of Evidence: B). (New
recommendation)

52
(Stroke 2010;41:2108-2129)
Which one for which condition?
 Calcium Channel Blocker Mechanism

Ca++ Ca++
Blocking
effect of CCB

Ca++ plus Calmodulin Ca++ plus Calmodulin

Myosin Kinase Myosin Kinase

Actin-Myosin Interaction
Contraction

Ca++ Ca++
54
 Classification Calcium Antagonists
Generation:
First Second Third Latest
Verapamil Felodipine Amlodipine Lercanidipine
Nifedipine Isradipine (hydrophilic) (lipophilic)
Diltiazem Nicardipine
Nimodipine
Nisoldipine
Nitrendipine
Prototype Tissue selectivity Tissue selectivity Tissue selectivity
gradual onset gradual onset
Plasma controlled membrane controlled
J Clin Basic Cardiol 1999;2:155
Comparison between Calcium Antagonist
Drug Coronary Suppression Suppression Suppression
Vasodilation of Cardiac of SA Node of AV Node
Contractility

Verapamil ++++ ++++ +++++ +++++

(phenylalkylamine)

Diltiazem +++ ++ +++++ ++++

(benzothiazepin)

Nicardipine +++++ 0 + 0
(dihydropyridine)

TS Kerins DM. Goodman Gilmans.10th ed.2001:843-870

Calcium Channel Blockers ( CCBs )

Dihydropyridine ( DHP )
Nifedipine, Amlodipine, Felodipine
Non-Dihydropyridine ( NDHP )
Diltiazem, Verapamil

OPIE, 2001
*
Nicardipine Diltiazem
(dihydropyridine) (benzothiazepine)
Peripheral
Vasodilation1
+++++ +++
Coronary
Vasodilation2
+++++ +++
Suppression
of SA Node2 + +++++
Suppression
of AV Node2 0 ++++
Suppression
of Cardiac Contractility2 0 ++

1. Frishman WH, et al. Med Clin North Am. 1988;72:523-547.

2. Adapted from Goodman and Gilmans: The Pharmacologic Basis of Therapeutics. 9th ed. 2001.
 NICARDIPINE and DILTIAZEM

NICARDIPINE DILTIAZEM

Target organ Arteriole (ca Channel) Arteriole (ca Channel)

Clinical effect Vasodilatation : BP Vasodilatation : BP

decreased decreased
Heart Rate
* Diltiazem and Nicardipine on HR of
Hypertensive emergency
Heart Rate (beat/minute)
patients
< 60 60 - 80 > 80

Nicardivine I.V. Diltiazem I.V

61

Kesimpulan: seluruh responden menurunkan
TD pada pasien ICH secara agresif melebihi dari
yang direkomendasikan oleh guideline lokal
maupun dari negara barat . Nicardipine adalah
preparat antihipertensi yang terbanyak
digunakan.
Questionnaires regarding antihypertensive treatment strategies for
Intracerebral hemorrhage in Japan (SAMURAI study):550 hospitals
In conclusion, the present Japanese respondents , especially neurosurgeons, lower BP more
aggressively than recommended in domestic and62western guide lines for managing acute ICH
63
NICARDIPINE
64
 NICARDIPINE
CHARACTERISTIC
1. VASOSELECTIVITY
Nicardipine selectivity 30.000 x in smooth muscle cells
blood vessels compared with myocardium
2. Myocardial depression (-)
3. Negative inotropic (-)
4. Rapid and stable antihypertensive effects, reduce blood
pressure gradually < 25% in 2 hours, minimal effects to
heart rate
5. Increase blood flow in major organ
65 : Renal, coroner,
 Nicardipine increase organ blood flow
Pharmacodynamic action

Perdipine: 3 g/kg/min 20 min

(%) Mean blood Vertebral Coronary (Hypertensive patients, n = 9)
Blood flow change rate

Renal
60 pressure artery
blood flow
blood flow
blood flow
Baseline value
40
Mean blood pressure 103 11 mmHg
Vertebral artery
20 183 65 mL/min
blood flow
Renal artery
563 29mL/min
Mean blood pressure

0 blood flow
Coronary artery
change rate

121 42 mL/min
blood flow
-10

-20
(%) 66 Scientific Meeting of the Japanese Society of Hypertension: 1997)
(Shoji Suzuki, et al., The 20th Annual
 Comparison Study with IV Diltiazem

Subjects:
Patients requiring a rapid reduction in BP
(DBP 115 mmHg)
Design:
Multicenter, randomized, single-blind comparative study
Dosage
Nicardipine: Started at 0.5 g/kg/min
Increased up to 10 g/kg/min if necessary
Diltiazem: Started at 5 g/kg/min
Increased up to 15 g/kg/min if necessary
68 Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437
Duration of drug administration
 Stability of antihypertensive effect of
Nicardipine is better than Diltiazem
Stability Effect

120
100 95.8
Perdipine
Diltiazem
80 69
%

60
40 24.1
20 6.8
4.2 0
0
Stable Slightly unstable Undeterminable

69 Yoshinaga K. et al. Igaku no Ayumi 1993: 165:437

 NICARDIPINE
Nicardipine injection 10 mg

NICARDIPINE
DOSIS DOSE
PERDIPINE
DIV Bolus
(g/kg/min) (g/kg)
Acute hypertensive crises during surgery 2 - 10 10 30

Hypertensive emergencies 0.5 6

Acute hypertensive crises during surgery

Hypertensive emergencies

0.5 1 2 6 (g/kg/min) 10

70
 Dosage and Administration
Start with the lowest dose.
Eg 0.5 mcg/BW/min 15 drops monitoring, if in
5-15 minutes theres no significant blood pressure
reducing
Increasing drip until 20 drop , and then can be
increased until desirable blood pressure achieved
(about 3-5 drops each after monitoring)
Monitoring blood pressure and heart rate frequently
71
Before choose to switch to oral, 1 hour before
 NICARDIPINE
The 1st line treatment of Hypertensive Emergency

Solution could be used :

Sodium Chloride / NaCl Solution couldnt be used
Sodium bicarbonat
( OTSU-NS : 100/250/500 ml ) Ringer Laktat
Dextrose 5%
( OTSU-D5 : 100 / 250 / 500 ml )
Glucose 5%
Potacol R 72
Summary
To recent consensus, decreasing BP in
acute haemorrhagic stroke is
recommended.
Choose parenteral antihypertensive
drugs and do the BP control cautiously
Nicardipine has been demonstrated to
be an effective agent for the control of
BP in patients with ICH as well as SAH.
73