PATHOPHYSIOLOGY and MANAGEMENT

HYPERGLYCEMIA IN
ACUTE ISCHEMIA STROKE (AIS)

Moch Syahrial P*)

*) Neurologist Gambiran General Hospital

Definitions of Stroke
Stroke was defined as rapidly developed
signs of focal (or global) disturbance of
cerebral function lasting >24 hours
(unless interrupted by surgery or death),
with no apparent nonvascular cause

Thorvaldsen P, Asplund K, Kuulasmaa K, et al., 1995. Stroke Incidence, Care Fatality, and Mortality in the WHO
MONICA Project. Stroke 26: 361-7

Stroke and Hyperglycemia

Up to 20% to 50% of acute stroke patients
have hyperglycemia.
Several studies have demonstrated a
detrimental effect of acute hyperglycemia on
outcome from ischemic stroke.
Increased admission glucose levels in acute
stroke have also been associated with longer
in-hospital stay, increased cost, and mortality.

Kolawole W, Njide O, Franck O, et al., 2002. Effect of Admission Hyperglycemia on Short-Term Outcome in Adult
Nigerians with a First Acute Ischaemic Stroke. African Journal of Neurological Sciences 26(2): 1-17

PATHOPHYSIOLOGY AIS

Detrimental Effect of Decreased CBF to

Brain Tissue

Aerobic Metabolism
Glucose + 2Pi + 2NAD
2Piruvat + 2ATP + 2NADH
Glucose + 6O2 + 36Pi + 36ADP
6CO2 + 36ATP + 42H20

Anaerobic Metabolism
Glucose + 2ADP + 2Pi
Lactate + 2ATP

ISCHEMIA

ISCHEMIA PREVENTS OXYGEN AND GLUCOSE DELIVERY

Acidosis in Infark Cascade

Gusev E, Skvortsova, 2003. Brain Ischemia. Plenum Publisher, New York

PATHOPHYSIOLOGY
HYPERGLYCEMIA IN AIS

Hyperglycemia after acute stroke may be

attributable to several underlying mechanisms:
1. A nonspecific reaction to acute stress
2. Autonomic, hormonal, and metabolic
alterations
3. Uncovering of underlying latent diabetes by
the acute stroke
4. Activation of the HPA-axis attributable to a
direct effect of brain ischemia on the pituitary
5. Irritation of the glucose regulatory centers in
the brain by a stroke.
Garg R, Chaudhuri A, Munschauer F, et al., 2006. Hyperglycemia, insulin, and Acute ischemic Stroke: A Mechanistic
Justification for a Trial of Insulin Infusion Therapy. Stroke 37: 267-273.

BERBAGAI STIMULUS SEBAGAI FAKTOR STIMULASI AKSIS HPA

COGNITITVE STIMULI:
FISIK, EMOSI, KIMIA

NON COGNITIVE STIMULI:

VIRUS, BAKTERI, TUMOR
BRAIN & NERVUS
SYSTEM

IMMUNE
SYSTEM

NEUROENDOCRINE
SYSTEM

HYPOTHALAMUS
CRH

LYMPHOCYTE &
MACROPHAGE
CYTOCINES

NEGATIVE FEEDBACK

ANTERIOR PITUITARY GLAND

ACTH

ADRENAL CORTEX

NEGATIVE FEEDBACK

GLUCOCORTICOID HORMONES

Hypothalamus
Pituitary

IL-1, TNF, IL-6

M
cytokine

Lymphocyte

cortisol

IL-6

FEVER

ACTH
Adrenal gland
Corticosteroid

Acute phase proteins

Complement
activation

DeKeyser F, 2003, AACN Clinical Issue; 14:25-32

Flint R W, 2004. Emotional Arousal, Blood Glucose Levels, and Memory Modulation: Three Laboratory
Exercise in Cognitive Neuroscience. The Journal of Undergraduate Neuroscience Education (JUNE) 3 (1):
A16-A23.

Factors Promoting Glukoneogenesis

Soegondo S, 2001, Homeostasis Glukosa Darah pada Stroke, Dalam: Alw I, Setiati S, Sudoyo A, dkk., Pertemuan Ilmiah
Tahunan Ilmu Penyakit Dalam. Pusat Informasi dan Penerbitan Bagian Ilmu Penyakit Dalam FK UI, hal.: 115-121

DETRIMENTAL EFFECT
HYPERGLYCEMIA ON AIS

Vascular Effect Hyperglicemia in Stroke

Martini S R, Kent T A, 2007. Review Article: Hyperglycemia in Acute Ischemic Stroke: A vascular Perspective.
Journal of Cerebral Blood Flow 7 Metabolism 27: 435-451.

Factor XIIa

Factor XII

Prekallikrein

Tissue activator
(tPA)

Kallikrein

(Endotelium)

PAI-1

inhibition

Plasminogen

Plasmin

(Inactive)

(Active)
-2-Antiplasmin
-2-Macroglobulin

Biodegradation
(Faktor V, VII, IX, dll)

Fibrino(geno)lysis

FDP Formation
Handin, R.L, 2005, Harrisons Priciples of Internal Medicine, 16th Ed. Editors: Kasper, D.L, MD. et all, Bleeding and
Thrombosis, Mc Graw Hill, New York, 53:337-342

Detrimental Effect of Reperfusion under

Hyperglycemic Conditions

Martini S R, Kent T A, 2007. Review Article: Hyperglycemia in Acute Ischemic Stroke: A vascular Perspective. Journal of Cerebral Blood
Flow 7 Metabolism 27: 435-451.

Garg R, Chaudhuri A, Munschauer F, et al., 2006. Hyperglycemia, insulin, and Acute ischemic Stroke: A Mechanistic
Justification for a Trial of Insulin Infusion Therapy. Stroke 37: 267-273.

LPS bp
TLR4
CD14

MD-2

GU
N

My D88
IRAK

TRAF6

THyperglicemia
UR

NIK/MKK

M
IKK
NF-KB
Target Genes

Guntur,2008;Sepsis Forum

LPS
TLR4
CD14

MD-2

My D88
IRAK

TRAF6
NF-KB

Target Genes

CYTOKINES

IL-6
TNF-

IL-12
IL-8
IL-1

22

IL1-,
TNF-

VCAM-1: Vascular Cell Adhesion Molecule-1

1
MMPs: Matrix Metalloproteinases

MCP-1: Monocyte Chemoattractant Protein-

Peter Libby, 2002, Inflamation in Atherosclerosis, Natuere Vol. 420, www.nature.com/nature

Matrix Metalloproteinases (MMPs):

Degrade extracellular matrix that lends
strength to the plaques fibrous cap plaque
rupture as a consequence permits blood to
contact macrophage product (the potent procoagulant protein TF)
Reduction of laminin, endothelial barrier Ag,
and the zona occludens (maintain BBB)
increase permeability BBB, leakage of plasma
protein and inflamatory cell
Garg R, Chaudhuri A, Munschauer F, et al., 2006. Hyperglycemia, insulin, and Acute ischemic Stroke: A Mechanistic
Justification for a Trial of Insulin Infusion Therapy. Stroke 37: 267-273.

INSULIN THERAPY IN AIS

WITH HYPERGLYCEMIA

Garg R, Chaudhuri A, Munschauer F, et al., 2006. Hyperglycemia, insulin, and Acute ischemic Stroke: A Mechanistic
Justification for a Trial of Insulin Infusion Therapy. Stroke 37: 267-273.

LPS bp
TLR4
CD14

MD-2

GU
N

My D88
IRAK

TRAF6

Insulin Treatment
TU
R

NIK/MKK

M
IKK
NF-KB
Target Genes

Guntur,2008;Sepsis Forum

27

PENATALAKSANAAN HYPERGLYCEMIA
PD STROKE ISKEMIK AKUT

Rute Pemberian Insulin

Jenis Pasien di RS :
1. Perawatan ICU: insulin i.v
2. Perawatan di ruangan: insulin s.c

PERKENI, 2007. Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus. Pusat Penerbitan ilmu Penyakit
Dalam, Fakultas Kedokteran Universitas Indonesia, Jakarta.

Target Kadar Gula Darah

Populasi Pasien

Kadar Glukosa Darah

(mg/dL)

Pasien kritis bedah

90 - 110

Pasien kritis nonbedah &

bedah tdk kritis

90 - 140

PERKENI, 2007. Petunjuk Praktis Terapi Insulin pada Pasien Diabetes Melitus. Pusat Penerbitan ilmu Penyakit
Dalam, Fakultas Kedokteran Universitas Indonesia, Jakarta.

Target Kadar Gula Darah (cont)

Kadar glukosa darah pd pasien stroke
berkisar 80 140 mg/dL

Adams HP, Zoppo G, Alberts M J, et al., 2007, Guidelines for the Early Management of Adults With Ischemic Stroke,
Stroke 38: 1655-

3. Protokol IV Infus Insulin

Panduan Umum:
Target kadar glukosa darah: 80-180 mg/dL
(80-110 untuk intensive care)
Standar drip insulin 100 U/100 ml 0.9%
NaCl via infus (1U/1ml)

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Cairan Intravena:
Kebanyakan penderita perlu 5-10 g
glukosa.
Mis: D5% atau D5-1/2 saline pada
100-200 ml/jam.

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Algoritma 1: mulai untuk kebanyakan penderita

Algoritma 2: untuk penderita yg tdk dpt
dikontrol dgn algoritma 1
untuk penderita diabetes yg
menerima insulin > 80 U/hari sbg
outpatient
Algoritma 3: untuk penderita yg tdk dpt
dikontrol dgn algoritma 2
Algoritma 4: untuk penderita yg tdk dpt
dikontrol dgn algoritma 3
PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

Glukosa drh
(mg/dL)

(cont)

Kecepatan Infus Insulin (U/jam)

Algoritma 1

Algoritma 2

Algoritma 3

Algoritma 4

70-109

0.2

0.5

1.5

110-119

0.5

120-149

1.5

150-179

1.5

180-209

210-239

12

240-269

16

270-299

10

20

300-329

12

24

330-359

14

28

>360

12

16

28

< 60
< 70

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Evaluasi Penderita
Periksa glukosa darah kapiler per jam
s/d target kadar glukosa yg diinginkan
selama 4 jam, kemudian diturunkan tiap
2 jam, bila tetap stabil dikurangi tiap 4
jam.
Pasien kritis evaluasi tiap jam (walau
glukosa darah stabil)
PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Peralihan ke Insulin Subkutan

Berikan insulin short-acting atau rapid
acting insulin s.c 1-2 jam sebelum
menghentikan infus insulin i.v.
Dosis insulin basal dan prandial harus
disesuaikan dgn kebutuhan penderita.

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

Glukosa drh
(mg/dL)

(cont)

Kecepatan Infus Insulin (U/jam)

Algoritma
Do Rendah

Algoritma 2
Do Sedang

Algoritma 3
Do Tinggi

150-199

200-249

250-299

300-349

10

>349

12

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Algoritma Do Rendah: untuk pasien yg

membutuhkan < 40 U insulin/hari
Algoritma Do Sedang: untuk pasien yg
membutuhkan 40-80 U insulin/hari
Algoritma Do Tinggi: untuk pasien yg
membutuhkan > 80 U insulin/hari

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Pengobatan Hipoglikemia
Hipoglikemia bila glukosa darah < 60
mg/dL.
Hentikan insulin drip.
Berikan dekstrose 50% dalam air
(D50W) i.v
Bila sadar: 25 ml (1/2 amp)
Bila tdk sadar: 50 ml (1 amp)
PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

3. Protokol IV Infus Insulin

(cont)

Periksa ulang glukosa darah tiap 20 mnt

& berikan ulang 25 ml D50W i.v bila
glukosa darah < 60 mg/dL
Mulai lagi dgn insulin drip bila kadar
glukosa darah > 70 mg/dL (2x periksa).
Mulai insulin drip dgn algoritma lebih
rendah

PERDOSSI, 2007. Kedaruratan Medik Stroke Akut. Guideline Stroke. Edisi revisi.hal. 59-66

TERIMA KASIH

ENDOTOKSIN

LPS bp
TLR4
CD14

MD-2

GU
N

My D88
IRAK

TRAF6

inhibition
TAntioksidan
UR

NIK/MKK

M
IKK
NF-KB
Target Genes

Guntur,2000;Patobiologi Surabaya