what we learn from the

newest evidence
Paulus
?
Neurology Sugianto
Dept, Dr. Soetomo Hospital/
Faculty of Medicine, Airlangga
University,
Surabaya
Stroke is the leading cause of Death among Indonesians, accounts
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 u
Indonesia
The mean age of stroke patients is 58.8 years.
Currently, there are only 40 stroke units in Indonesia, and all locat
in city hospitals which have neurology, neurosurgery, neuroimagin
and rehabilitative services

2
 1,4%

18,5% Sub Arachnoid

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

1. Ministry of Health. Riset Kesehatan Dasar (RISKESDAS). Indonesia: Ministry of Health: 2007.
2. Misbach J, Ali W. Stroke in Indonesia: a first3large 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 o
disability
Stroke is the third leading cause o
death
67% of stroke is ischemic
4
No. Underlying Disease Hemorrhagic Ischemic
1 Previous Stroke stroke29,4 Stroke
35,8
2 Transient Ischemic 3,1 4,4
3 Attack 1,0 1,2
4 Peripheral Arterial 71,9 63,8
5 Disease
Dyslipidemia 10,2 15,1
6 Hypertension
Diabetes 11,2 24,5
7 Mellitus 1,3 3,2
8 Atrial Fibrilation 1,1 2,1
9 Angina
Infarct Pektoris 1,9 2,8
10 Miokard
Heart valve 0,3 0,8
11 disorder 2,0 3,0
12 Heart failure
On Antithrombolytic 2,2 5,1
13 agent 1,5 1,9
Anemia
Stroke Registri 2012-
RISK FACTORS HEMORRHAGIC
0,3 Stroke based
STROKE on Disease and Stroke
Underlying
1,1 1,9 type.
2 2,2 1,5
Stroke
1,3 sebelumnya
11,2 29,4 TIA
10,2 3,1
1 Peripheral
Arterial
Hypertension Disease
Hipertensi

Dislipidemia
71,9
Diabetes
Mellitus
7 Stroke Registri 2012-
2013
CVA Infark CVA Infark + rtPA CVA
bleeding

8
Type of Infarct Blood
Stroke
Pressure
AHA-ASA reduced
should beif ~
Guideline EUSI
Type of ICH guidelines
Stroke SAH Blood
should be
Pressure
AHA-ASA
Guideline EUSI
controlled early
9
Which one for which
condition?
 Classification Calcium Antagonists
Generation:
First Second Third Latest
Verapamil Felodipine Amlodipine
Nifedipine Isradipine Lercanidipine
Diltiazem Nicardipine (hydrophilic) (lipophilic)
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 0 ++
Contractility2
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
 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
Heart Rate
emergency
patients
<60
(beat/minute)
60 - 80 > 80

Nicardivine I.V. Diltiazem I.V

Blood Pressure lowering using Nicardipine
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 agent
1

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 a
SBP < 185 mm Hg and DBP < 110 mm Hg. After treatm
with fibrinolysis, the SBP should be maintained < 180 m
Hg and the DBP at < 105 mm
23 Hg for 24 1,2
Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 25
1
2
25
Decreasing Blood Pressure
in
Certain Conditions
1. Acute ischemic
stroke *):; DBP >
SBP >220
2. 120.
rtPA candidate
**):
SBP >185 ; DBP > 110 (Class I; Level of Evidence B) and
maintained
3. below 180/105
Acute for at least
hemorrhage the first
stroke : 24 hours after iv rtPA
treatment
SBP > 180 ; DBP > 100 or MAP
4. >145
* ASA Guideline, May

Acute Stroke with
Hypertensive 26
2007
: Class I, Level of
encephalopathy
hypertension : evidence C.
 Candidates
Patient for
otherwise Acutefor
eligible Reperfusion
acute
Therapy
except that BP
reperfusion is >185/110
therapy
Labetalol
mm Hg: 1020 mg IV over 12 minutes, may repea
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,
Other agents (hydralazine, enalaprilat,
adjust to be
etc) may maintain proper BP limits; or
If considered when appropriate
BP is not maintained
27
at or below 185/110
(AHA/ASA mm
: Stroke 2013)
 Candidates for Acute Reperfusion
Management
Therapy of BP during and after rtPA or
reperfusion
other acute therapy to maintain BP at or below
Monitormm Hg:
180/105
every
BP : 15 minutes for 2 hours from the start of rtPA
therapy, then
every 30 minutes for 6 hours, and then
If systolic
every hour for 16 hours
BP >180230 mm Hg or diastolic BP >10
mm Hg
120
If
UseBPIVnot
preparation
controlled or diastolic BP >140 mm H
28

sodium (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
2. infusion, with frequent
If SBP is >180 mm Hg orBP MAPmonitoring
is >130 mm everyHg5and
min.there
is
the possibility of elevated ICP, then consider
monitoring
ICP and reducing BP using intermittent or continuous
intravenous
3. If SBP is 180medications
mm Hg or MAP while maintaining
is 130 mm Hg and a cerebral
there is
note
perfusion pressure >60 mm Hg.
evidence of elevated ICP, then consider a modest
reduction
to BP
of control
(eg, BP
MAPandof clinically
110 mm reexamine
32 Hg or targettheBP patient
of 160/90every
mm
min.
15
Hg) (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 saf
(Class I; Level of Evidence A) and can be effective for
improving functional outcome (Class IIa; Level of
Evidence
BP shouldB).be (Revised
controlledfrom
in allthe previous
ICH patients guideline
(Class I;
Level of Evidence A). (Revised from the
previous
Measures to control BP should begin immediately after
guideline)
ICH onset (Class I; Level of Evidence A). (New
35

recommendation) A long-term goal of(SBPtroke<1302010;4m

Summary
To recent consensus, decreasing BP in
acute
220
ischemic stroke is recommended if
systolic >
mmHg or diastolic > 120 mmHg.
To recent consensus, decreasing BP in
Patient otherwise eligible for acute
acute
reperfusion
Choose parenteral
haemorrhagic antihypertensive
stroke is recommended.drugs
therapy
and
do except that BP is >185/110 mm
36 the BP control

Hg
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 agent
1

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 a
SBP < 185 mm Hg and DBP < 110 mm Hg. After treatm
with fibrinolysis, the SBP should be maintained < 180 m
Hg and the DBP at < 105 mm
45 Hg for 24 1,2
Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 25
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 ca
be implemented in the next 24 to 48 hours
Exceptions :
o Ischemic stroke
o Aortic dissection SBP should < 100 mmHg
46
Chobanian AV et al, The JNC 7 report, JAMA 2003;389: 25
Blood Pressure reduction target
crisis hypertensive patients:
* Parenteral anti hypertension is giv
based on the procedure of cris
hypertensive treatment with MA
reduction 20-25% from the baseline in t
first hour.
Konsensus Penanggulangan Krisis Hipertensi (InaSH 2
B. Diltiazem (Herbesser) IV (50 mg/ampul)
* Diltiazem 10mg IV given by bolus in 1-3 m
followed by drip infusion 50 mg/jam in 20 menit.
* When the BP reduction achieve at >20% from
baseline, the dosage is adjusted to 30 mg/jam u
the BP reduction target achieved.
* Followed by maintenance dosage 5-10 mg/ja
observed in 4 hours, if stabil switch to oral.
* Precaution Konsensus
to the patients with AV Block and He
Penanggulangan Krisis Hipertensi (InaSH 2
 * Drugs used in the treatment of
emergency
* hypertension
Clonidin (InaSH
(Catapres) 2008, CHEST 200
IV (150
* mcg/ampul)
Diltiazem (Herbesser IV); 50 mg/ampul
Nicardipin (Perdipin IV (2 mg dan 10
mg/ampul)
Nitroprusside (Nitropress,
Labetalol (Normodyne) IV* Nipride) lV
Nitroprusside in drip infus with dosage
0.25-10.00
dosis mcg/kg/menit
Nitogliserin
(nitrat) Chest 2007;131;1949-1962
Konsensus Penanggulangan Krisis Hipertensi (InaSH 2
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
2. infusion, with frequent
If SBP is >180 mm Hg orBP MAPmonitoring
is >130 mm everyHg5and
min.there
is
the possibility of elevated ICP, then consider
monitoring
ICP and reducing BP using intermittent or continuous
intravenous
3. If SBP is 180medications
mm Hg or MAP while maintaining
is 130 mm Hg and a cerebral
there is
note
perfusion pressure >60 mm Hg.
evidence of elevated ICP, then consider a modest
reduction
to BP
of control
(eg, BP
MAPandof clinically
110 mm reexamine
51 Hg or targettheBP patient
of 160/90every
mm
min.
15
Hg) (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
Nifedipine Isradipine Lercanidipine
Diltiazem Nicardipine (hydrophilic) (lipophilic)
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 ++++ ++++ +++++ +++++

(phenylalkylamin
e)

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 0 ++
Contractility2
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
 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
Heart Rate
emergency
patients
<60
(beat/minute)
60 - 80 > 80

Nicardivine I.V. Diltiazem I.V

61

Kesimpulan: seluruh responden
TD pada pasien ICH secara agresif
menurunkan
melebihi dari
yang direkomendasikan oleh guideline
lokal
maupun dari negara barat . Nicardipine
adalah
Questionnaires regarding antihypertensive treatment strategies for
preparat
Intracerebral hemorrhage antihipertensi
in Japan (SAMURAI yang terbanyak
study):550 hospitals
In conclusion, the present Japanese respondents , especially neurosurgeons, lower BP
62 digunakan.
aggressively than recommended in domestic and western guide lines for managing acu
63
NICARDIPINE
64
 NICARDIPINE
CHARACTERISTIC
1. VASOSELECTIVITY
Nicardipine selectivity 30.000 x in smooth muscle
cells
2. blood vessels compared with myocardium
3. Myocardial depression (-)
Negative inotropic
4. (-)
Rapid and stable antihypertensive effects, reduce
blood
pressure gradually < 25% in 2 hours, minimal effects
to
5. Increase blood flow in major organ : Renal, coroner,
65
 Nicardipine increase organ blood
flow
Pharmacodynamic action
Perdipine: 3 g/kg/min 20
(%) Mean blood Vertebral min
Coronary (Hypertensive patients, n =
Renal
60 pressure artery
blood flow
blood flow
9)
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
0 blood flow
Coronary artery
121 42 mL/min
blood flow
-10

-20
(%) 66 Annual Scientific Meeting of the Japanese Society of Hyperte
(Shoji Suzuki, et al., The 20th
1997)
 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
 Stability of antihypertensive effect of
Nicardipine is better than Diltiazem
Stability
Effect
120
100 95.8 Perdipine
80 69 Diltiazem
60
40 24.1
20 4.2 6.8
0 0
Stable Slightly unstable Undeterminable

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

 NICARDIPINE
Nicardipine injection 10 mg

DOSISNICARDIPERDIPINEPINE DOSE
D IV Bolus
( g /k g /m ( g/kg)
A c u te h y p e rte n s iv e c ris e s d u rin
in 2) - 1 10
g s u rg e ry 0
0.5 30
H y p e rte n s iv e e m e rg e n c ie s 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
5-
15 minutesiftheres
monitoring, in no significant blood
reducing
pressure
Increasing drip until 20 drop , and then
can be
increased until desirable blood pressure
achieved blood pressure and heart rate
Monitoring
(about 3-5 drops each after monitoring)
frequently
71
Before choose to switch to oral, 1
 NICARDIPINE
The
st 1
line treatment of Hypertensive Emergency
Solution could be used :
Sodium Chloride / NaCl Solution couldnt be
used
) Ringer
(OTSU-NS : 100/250/500 mlSodium Laktat
bicarbonat
Dextrose 5%
(OTSU-D5 : 100 / 250 / 500 ml )
Glucose 5%
Potacol 72
Summary
To recent consensus, decreasing BP
acute
in haemorrhagic stroke
is
Choose parenteral antihypertensive
recommended.
drugs and do the BP control
cautiously
Nicardipine has been demonstrated
toan effective agent for the control
be
BP in patients with ICH as well as
of 73
SAH.