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INTRODUCTION

Stroke has become the third leading cause of death after heart disease and cancer as well

as lead to long-term disability that causes dependency in socio-economic.1,2

The American

Heart Association and American Stroke Association defines ischemic stroke as an episode of

neurological dysfunction caused by focal brain infarction, spinal cord, and retina. Cell death

due to ischemia, based on pathological, imaging, or clinical evidence and other objective

evidence in the vascular distribution based on symptoms that persist 24 hours and without

an obvious cause of death other than stroke vaskular.1

Research that has been done by ASNA ( ASEAN Neurological Association ) in Indonesia

, in patients with acute ischemic stroke at 28 hospitals (hospital -based study) showed that

ischemic stroke or hemorrhagic stroke is the most frequent of all stroke cases.6Male - more

men than women with the highest prevalence in the age of 45-64 years ( 54.2 % ) .6

According to stroke Subtype Classification Data Bank , the Harvard stroke Registry

classification , the National Institute of Neurological Disorders and stroke ( NINDS ) thefrequency of ischemic stroke thromboembolism is 77 % .

7,8This will cause disruption in the

blood flow to the brain, so it will deprive the essential nutrients such as oxygen and glucose,

resulting in ischemic stroke.9 , 10

In the ischemic state, especially during reperfusion or

reoxygenation it will be an increase in free radical formation . Free radicals are highly

reactive and tend to react with other molecules to find a pair of electrons so that it becomes a

more stabil.13,14

Free radicals can react with lipid membrane, proteins and DNA peroxidation

and alter the structure and function that caused the cell death.15 -17

1.1

The Mechanism of Free Radical Formation in Acute Ischemic StrokeMost of the damage caused by cerebral ischemic the lipids contained in the cell

membrane through lipid peroxidation and phospholipase activity. Cerebral ischemia resulted

in the rate of release of fatty acids (especially arachidonic acid) because of phospholipase

enzyme. Calcium-dependent cytoplasmic PhospoLipase A2 (cPLA2) is activated by the

influx of Ca2 + ions into the cell after a few minutes of ischemia events. cPLA2 oxidized

arachidonic acid release (in large amounts in the cell membrane). Lipooxgenase enzymes

form lipid hydroperoxide (Rooh) which can cause lipid peroxidation. Arachidonic acid itself

has an effect on mitochondrial uncoupling in addition to the direct inhibition of

mitochondrial respiratory enzymes and triggers the formation of free radical.56, 57

Free

radicals are atoms or molecules that there is at least one unpaired electron and the outer

orbital. Many free radicals are formed in the brain ischemia, due to the release of ferritin iron

ions when ischemia.

Diagram 1 : Free radicalsformation in Ischemic Stroke57


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(Source : hanafy&selim, 2012)57

1.2 Total Antioxidant Status (TAS)

Antioxidants are substances or nutrients that can prevent or slow down the oxidative

damage to the body. The use of oxygen in the body's cells naturally produce free radicals and

can cause damage. Antioxidants act as "free radical carrier" prevent and repair damagecaused by free radicals. Free radicals are highly reactive oxygen species derived from

environmental, dietary and of normal biochemical processes that occur in the body. Free

radicals occur when molecular oxygen is converted to sound unstable form of oxygen is

highly reactive, can do a lot of damage to reprogram the DNA so that free radicals can attack,

damage and ultimately destroy any material including sensitive cells and tissues throughout

the body.

Antioxidants consist of various components of both intracellular (inside the cell /

endogenous), and extracellular (outside the cell / exogenous). Antioxidants by type consists

of antioxidant enzymes and vitamins. Antioxidant enzymes include superoxide dismutase

(SOD), catalase and glutathione peroxidase (GSH.Prx). Antioxidant vitamins are more

popular as compared antioxidant enzymes, including alpha tocopherol (vitamin E), beta

carotene and ascorbic acid (vitamin C) .69, 71

There are three groups of antioxidants in the body:69, 71


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1. Primary Antioxidants (Antioxidants Primary). Works by preventing the formation of new

free radicals. Example: SOD (superoxide dismutase), GPx (glutathione peroxidase), and

metal-binding proteins (Metal Binding Protein) as Ferritin or ceruloplasmin, Zn (zinc).

2. Secondary Antioxidants (Antioxidants Secondary). Functioning capture of radicals and

prevent a chain reaction. Example: Vitamin E (alpha-tocopherol), Vitamin C (ascorbate),

beta-carotene, uric acid, flavonoids, bilirubin and albumin..

3. Tertiary Antioxidants (Antioxidants Tertiary). This type of antioxidant and tissue repair

cell damage caused by free radicals. Example: enzymes that repair DNA and methionine

sulfoxide reductase.

The balancing between antioxidants and free radicals is the key factor prevention of

oxidative stress triggered by two general conditions, the lack of antioxidant and free radical

overproduction. About the selection to measure anti oxidant status (SAT), several clinical

studies on antioxidants as neuroprotective agents, still have not looked successful, mainly

because of the blood-brain barrier (BBB) is very effective in protecting the brain from the

majority of endogenous chemical compounds or exsogen.

69, 71-73

1.3 National I nstitutes of H ealth Scale Stroke(NIHSS)

National Institutes of Health Stroke Scale ( NIHSS ) is a systematic measurement that

is designed to measure the most frequent neurological deficits seen in stroke patients. NIHSS

was designed to standardize and document the neurological test that is reliable and valid ,

which can be carried out in less than 10 minutes . NIHSS - 3 is often used in research to

measure the output of acute stroke and neurological recovery in stroke patients . NIHSS

score range 0-42 has the interpretation of a mild stroke severity NIHSS 1-4 when , with the

score 5-15 strokes were severe strokes with a score of 15-20 and very severe strokes with a

score above 20 . Domain NIHSS assessment consists of 11 items integration of componentchecks the level of consciousness , cranial nerves , motor strength , sensory , language ,

attention and clinical examination serebelar.130

New approach for NIHSS score is used as a

measure of the output of an acute stroke, can be a tool of analysis and useful for

communication. At moderate stroke severity ( NIHSS baseline score 7-15 ) , an increase of at

least 55 % is the best predictor of functional independence at 3 months after acute stroke (

with a modified ranking scale / mRS < or = 2 ) .131 , 132

Stroke severity, as assessed by NIHSS total score, is an important factor affecting the

length of stay (Length Of Stay) acute stroke patients. Each increase of 1 point in total NIHSS

score, length of stay will increase by approximately 1 day for patients with mild or moderate

neurological disorders (score of 0 to 15 points), while LOS decreased by approximately 1

day for patients with severe neurological disorders (scores> 15 points).

Modified NIHSS scale proved related to the Bartel Index ( BI ) , Modified ranking

scale ( mRS ) , and Glasgow Outcome Score ( GOS ) at 90 days after stroke . ATLANTIS

trial using the NIHSS as a prognosis of secondary end points , whereas the NINDS study ,

NIHSS is used as part of the global primary end points , along with BI , mRS , and GOS


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which allows patients to be assessed on realistic goals while maintaining generalization .

Despite the potential for increased visibly in the statistics , the scale of neurological disorders

have been rarely used as primary end points . In contrast , regulatory authorities tend to favor

research using disability scale . The European Medicines Evaluation Authority ( EMEA ) 31

accepts that the neurological scale output as the secondary efficacy end points . The decrease

in scale is more sensitive to changes in patient status and may be more relevant for phase I

and II trials . Disability scale was considered more relevant in the phase III stroke study . The

use of NIHSS scores beneficial for end point at 90 days and can be used in clinical trials of

treatment of acute stroke phase , more powerful to assess the benefits of treatment tersebut.133

NIHSS scores on the stroke of the blockage in basilar , internal carotid and middle

cerebral artery M1 and M2 segments blockage ( occlusion central ) higher than those located

more peripheral , does not look or absence of obstruction . Patients with NIHSS scores > 10

had a positive predictive value ( Positive Predictive Values) for carotid artery occlusion

showed 97 % and 96 % in the vertebrobasilar stroke . With NIHSS scores < 12 , the PPV to

find a central occlusion was 91 % . In multivariate analysis , the sub items such questionsNIHSS level of consciousness , eye movement , motor strength of the lower extremities and

neglect is a predictor of central obstruction . There is a significant relationship NIHSS scores

and the presence and location of the blockage of blood vessels . With NIHSS scores < 10 ,

occlusion of vessels is likely to be seen on arteriography , and with a score of < 12 , the

location of the possibilities in the central nervous system . NIHSS has been widely used in

research to assess the severity of acute ischemic stroke and is a tool that has been validated to

predict stroke output 2-6 . In particular has been used in trials of thrombolysis to determine

inclusion and exclusion criteria in patients receiving active therapy trombolisis.134

HYPOTHESIS2.1 Major Hypothesis

Snakehead fish extract may improve protein status, the status of oxidative stress and total

antioxidant status (SAT), and can fix the output of clinical acute ischemic stroke as measured

by the NIHSS score.

2.2 Minor Hypothesis

1. Snakehead fish extract will increase the levels of total antioxidant status (SAT) acute

ischemic stroke patients.

2. Snakehead fish extract will reduce oxidative stress with decreased levels of

malondialdehyde (MDA) acute ischemic stroke patients.

3. Changes in levels of protein status (Alb, TTR, TFR, RBP) associated with changes in total

antioxidant status (SAT) and the levels of malondialdehyde (MDA).

4. The decrease in NIHSS scores associated with decreased levels of malondialdehyde

(MDA) and increased total antioxidant status (SAT).

5. Decreased levels of malondialdehyde (MDA) is associated with increased total antioxidant

status (SAT).


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DISCUSSION

3.1 Description of the studys location

The study was conducted at Dr Dr.Kariadi Semarang is a type A referral hospital with

978 beds and facilities have a stroke care unit facilities and wards specialized nerve .

Treatment of acute ischemic stroke patients in the department of dr . Kariadi standard therapy

has been carried out by the appropriate SPO . This research is a true double-blind

experimental design with pretest - posttest control group .

This study design can control the factors that may threaten the internal validity , such

as history , maturation , testing , intrumentation , regression , selection , mortality , and the

interaction between these factors faaktor . History validity threats can occur when conducting

research between the control group and the treatment was carried out in one session .

Implementation of this research carried out simultaneously ( simultaneous ) with random

allocation between the treatment and control groups .

Maturation and testing effects can be overcome by the use of a control group , as wellas to manifest equal randomization of samples between the control and treatment groups .

This study has a control group and randomization in the study sample . Researchers also tried

to compare the initial state of the sample status between control and treatment groups , the

results showed no significant differences in all the variables to be measured .

The validity of the instrumentation in this study controlled using fixed instruments are

the tools that ditera routine and the result is a print-out of quantitative data in the form of

fixed numbers with a certain degree of precision. Pre and post test examination conducted by

the same tools and methods. If there is data obtained from observations of the observer, is

always carried out by at least two observers were then calculated the value of clinical

agreement Kapanya. In this research, double blinding, in which researchers and researchsubjects do not know where and put into groups where the sample studied, so the results of

the study are expected to answer the research hypothesis is right.

Threats regresion effects addressed by calculating the value of different groups is

based on the calculation of the mean of the group and then performed different test. Control

of the internal validity of the selection effects are also conducted in this study. Selection of

samples obtained through the recruitment of a stroke unit and from general wards, through

the inclusion and exclusion criteria. The number of samples is calculated sample-based

epidemiological studies that sampling handbook for health research published by the World

Health Organization (WHO). Subsequently the samples obtained randomization into the

study group.

Another validity threat mortality. Efforts by researchers to avoid adanyadrop-out and

mortality is by monitoring the presence of concomitant medication. Utililization health care

resources (hospital, emergency installation, and intensive care unit), and monitoring of side

effects and performance suspcion statuspasien. In addition, it also made continuous personal

contacts and subsidizing the purchase of snakehead fish extract to improve adherence and


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uptake of both EIG supplementation in patients. But the implementation of the study until the

end of the study still found death and drop-out in both groups and the control group both

treatment groups.

Based on the discussion of threats to the validity of the above, it is concluded that in this

study these factors can still be controlled. Therefore it could proceed itupenelitian for

hypothesis testing procedure.

3.2Interrater Clinical Agreement

NIHSS scores examination conducted by more than one examiner in 31 study

subjects (74%) in the ward.

The test results obtained Kappa value = 0.870, can be obtained expressed strong

conformity between the NIHSS examination examiner 1 and examiner 2. Correlation test

results demonstrate a strong correlation workup 1 NIHSS examiner to examiner 2 (r =

0.994), thus it can be concluded that the presence of high conformity between examiner 1

with examiner 2.

3.3 Characteristics of Research Subjects

This research has been conducted in the department of dr. Kariadi Semarang in the

span of six months, from May to October 2013. The study sample was obtained acute

ischemic stroke patients as much as 199 people met the study criteria and had been willing to

be a sample informed consent through approval in as many as 61 people. After

randomization obtained as many as 32 people as subjects in the treatment group and 29

subjects as a control group. In the treatment group obtained 10 subjects experienced a drop

out and one died while the control group experienced a 6 subjects dropped out and 2 subjects

died. Causes of drop out on the subject of the study in part because patients go homeforcibly, move the hospital or unwilling to continue his research.


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3.4 Consort (Consolidated Report of Tr ial)

3.5 Effect of Extracts Against Snakehead Fish total antioxidant status levels

The results showed that there was no significant difference in the mean levels of total

antioxidant status before treatment (SAT_1) between the treatment group and the control

group (p = 0.101). Levels of delta change () SAT showed no significant difference in both

groups. In the treatment group experienced a decline in descriptive look better, that is equal

to 0.0339 0.09118, while the control group decreased by -0.0060 0.03617. SAT test

results can be seen in Table 11.

random sampling alocation

Blood sampling and analysis of data kaPengukuran end (post-test) levels of MDA, SAT, TTR, RBP

and albumin TFR in the serum of acute stroke patients

32 subjects treatment group 29 subjects control group

Acute ischemic stroke patients (199 people )

Meet the inclusion and exclusion criteria (61 people)

Measurement of baseline (pre-test) levels of MDA,

SAT, TTR, RBP and albumin TFR in the serum of

acute stroke atients

Treatment of stroke patients received

standard acute stroke therapy based on

SOP RS.dr. Kariadi

Treatment of stroke patients received

standard therapy of acute stroke

interventions based SOP added fish

extract cork (EIG as much as 15 grams.

6 subjects drop out, 2 died10 subjects drop out, 1 died


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Table 11. SAT Measurement

Variable MeanSB; Median; Min-Max p

Treatment Group

(n=21)

Case Group

(n=21)

SAT_1

1,45640,14850; 1,459; 1,104 -

1,699

1,361050,211035; 1,376; 0,881 -

1,676 0,101b

SAT_2

1,49030,14596; 1,505; 0,973 -

1,682

1,355100,206869; 13,845; 0,893 -

1,659 0,007a

p= 0,056

p= 0,471c

SAT

0,03390,09118; 0,0170; -0,21

0,22

-0,00600,03617; -0,0030; -0,09

0,06 0,075b

aMann-Whitney U;

bIndependent sample t-test;

cPaired t-test;

dWilcoxon

Based on the analysis above can be seen that in the treatment group contained elevated

levels of albumin , transthyretin , transferrin , RBP , as well as the SAT , while MDA levelsdecreased . The control group showed an increase in RBP , transthyretin and albumin

transferrinsedangkan , MDA and SAT decreased.

Based on the analysis of the mean difference test on the control and treatment groups

showed that there were significant differences for all variables . These results indicate that

administration of EIG can increase levels of albumin , RBP , transthyretin , transferrin as well as

SAT and MDA levels were significantly lowered . MDA mean difference test before treatment is

meaningful , so as to confirm the effect of EIG on levels of albumin, transferrin , transthyretin ,

SAT and the difference in the levels of MDA was calculated with the following variables before

treatment . The results showed a decrease in the control group contained only albumin , MDA

and SAT are relatively small.

The treatment group showed there is a substantial improvement on levels of albumin ,

RBP , transthyretin , transferrin and SAT are relatively higher than the control group , while

MDA levels decreased visible . Analysis of the mean difference test on the delta of data between

the control and treatment groups showed that there were significant differences for all variables .

[ p < 0.05 ] The results showed that administration of EIG is able to increase the levels of

albumin , RBP , transthyretin , transferrin as well as SAT and MDA levels were significantly

lowered .

3.6 Effect of Snakehead Fish Extract to NIHSS ScoreTest results NIHSS scores when patients come to the hospital ( NIHSS_1 ) showed that

there was no mean difference between the two groups ( p = 0.363 ), in the treatment group mean

of 8.67 (SD = 4.39 ) tended to be higher than in the control group 7.57 (SD = 4.72 ) . Mann-

Whitney test results also showed no significant difference mean NIHSS scores after 7 days (

NIHSS_2 ) between the two groups ( p = 0.990 ) . Based on the measurement results showed that

there were differences in NIHSS scores were highly significant decrease in both groups .


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Treatment group were given extracts of catfish ( EIG ) showed a decrease in score of -4.14 +2.03

and whereas in the control group also just seen a decrease of only relatively small compared to

the treatment group , ie the change of decrease of -2.52 +1.81 . When analyzed per group , it

appears that there is significant improvement mean NIHSS scores after the 7th day of treatment

in both groups ( p < 0.001 ) ( Wilcoxon Signed Rank Test ) . The results of this analysis can be

seen in Table 12, 16 .

Tabel 12.Diffrence Between NIHSS score in Treatment and Control Group

Mean SB P

Control Case

NIHSS I ,574,728;7,0; 2-19 8,674,397;9,0;2-15 0,363

NIHSS II

NIHSS

5,054,631;3,0; 1-16

-4.14+2.03

4,523,234; 4,0; 0 -11

-2.52+1.81

0,990

0,007

3.7 Relationship Between NIHSS scores with protein status (albumin, transthyretin, and

Retinol Binding Protein Transferrin), Oxidative Stress Status Malondialdehyde (MDA),

and the status AntioksidanTotal (SAT)

The results of the bivariate correlation analysis with Spearman Rho correlation between

NIHSS examination scores with protein status, the status of oxidative stress and antioxidant

status are listed in Table 14

Tabel 14. Correlation Test Between NIHSS scores with protein status, status Oxidative Stress

and Antioxidant Status

Variabel P R

Changes in albumin levels 0.005* 0.426

Changes in transthyretin levels 0,005* 0.429

Changes in transferrin levels 0.050* 0.304

Changes in RBP level 0.431 -0.125

Changes in MDA 0.067 -0,286Changes SAT 0.379 0.141

*Uji Spearman rho

Spearman rho test results showed a significant association between NIHSS examination

scores with the status of the protein albumin, transthyretin levels, transferrin levels (p


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the change in NIHSS with transferrin weak (r 0.05).

Diagram 8. The correlation between albumin levels with Delta Delta NIHSS scores

Diagram 9. The correlation between levels Transthyretin and Delta NIHSS scores


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3.9 Effect of Snakehead Fish Extracts to Malondialdehyde levels (MDA) and Total

Antioxidant Unit (SAT)

The results of the study showed catfish extract highly significant decrease in the

levels of MDA ( p = 0.000 ) . In the group treated with the extract showed a change

catfish decrease of -110.70 79.352 . Analysis of the data of different test delta

between the control and treatment groups showed that there were significant

differences for all variables ( p < 0.05 ) The results indicate that administration of EIG

can increase levels of albumin , RBP , transthyretin , transferrin as well as SAT and

MDA levels were significantly lowered . This study was in accordance with previous

studies that evaluated the lipid profile , oxidative stress and antioxidants in patients

with stroke and ( transient ischemic attack ). TIA showed an increase in MDA levels of

blood sugar , total cholesterol , triglycerides , LDL , HDL cholesterol and a decrease in

serum , erythrocyte SOD and vitamin E when compared with the control group . Stroke

patients showed levels of oxidative stress are higher than TIA patients , characterized

by elevated levels of MDA were higher , and decreased levels of SOD and vitamin Eare lower than TIA patients . Correlation of test results obtained serum MDA levels and

levels of serum total cholesterol and LDL were significantly positively correlated.

MDA levels and serum vitamin E on TIA or stroke showed significant negative

correlation. Levels of serum MDA and SOD levels was not significant negative

correlation was found in patients with TIA and stroke . MDA serum showed an

increased difference bermaknapadastroke and TIA as well as an increase in lipid

peroxidation during the stroke and TIA .143

3.10 Relationship between NIHSS scores with protein status (albumin, transthyretin,

and Retinol Binding Protein Transferrin), Oxidative Stress StatusMalondialdehyde (MDA), and Total Antioxidant Status (TAS)

This study may indicate a significant correlation between albumin levels at the

time of initial entry with NIHSS scores of patients at the time of hospital admission ,

with a moderate degree of relationship ( r -0.409 with p < 0.05 ) . Correlation strength

was the relationships that means there is a tendency in the opposite direction to the

initial albumin levels were low, initial NIHSS scores will be higher or stroke is more

severe.

Cohort study of albumin in acute ischemic stroke showed that high serum albumin

levels associated with better functional output on the seventh day and low mortality

after 2 years . Research shows that higher levels would be better . Median NIHSS

scores ( interquartile range ) at the time of hospital admission was 4 ( 1-8 ) and the

median mRS scores ( interquartile range ) on day 7adalah 2 ( 1-3 ) . Sixty patients ( 13

% ) died during the follow-up period of 2 years on average . Serum albumin is

independently associated with a higher better results ( OR = 1.12 , 95 % CI = 1.05 to

1.20 , p = 0.001 ) . After adjusting for age , sex and NIHSS score on admission , serum


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albumin levels were associated with lower mortality ( OR = 0.88 , 95 % CI = 0.83-0.93

, p < 0.0001 ) .153 Serum albumin at admission had a significant association with

stroke functional output as measured by the NIHSS score. Serum albumin at admission

is an independent predictor of good functional ischemic stroke output akut.154 In

another study Cox regression analysis showed hypoalbuminemia on admission (hazard

ratio (HR) 2, p = 0.03), age (HR 1.06, p

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