Majalah Kedokteran Nusantara Volume 39 No.

4 Desember 2006 402

Changes of Ureum-Creatinin Level in Acute Stroke Patients
Treated with Mannitol in Department of Neurology, Medical
Faculty University of Sumatera Utara Haji Adam Malik Hospital
Medan Indonesia

Dalton Silaban, Rusli Dhanu, Darulkutni Nasution
Department of Neurology, Medical Faculty, Universitas Sumatera Utara
H. Adam Malik Hospital
Medan- Indonesia


Abstract: Background and objectives: mannitol is widely used to decrease intracranial pressure and
to alleviate the space occupying effect from intracranial hemorrhage. There are many complications
of mannitol usage, for example: electrolyte and fluid disturbance, cardiopulmonary edema. Mannitol
can also cause renal failure in therapeutic dose. The objective of this study is to determine the kidney
safety toward mannitol usage in acute stroke patients. Material and methods: this study is an
interventional study with prospective study data collecting method, toward all acute stroke patients
with increased intracranial pressure in Neurology ward of H. Adam Malik Hospital, between 2
January30 April 2005. Mannitol 20 % was administrated for 5 days. Serum ureum-creatinin level
was measured before administration, on the 2
nd
day, and on the 5
th
day after administration. Result: of
25 patients (16 males, 9 females) ; 9 patients had acute ischemic stroke and 16 had acute hemorrhage
stroke. Increasing of serum ureum level 1,40 times was observed on the 2
nd
day (p< 0.05) and 2.01
times on the 5
th
day (p< 0.05) and serum creatinin level was increased 1.32 times on the 2
nd
day (p<
0.05) and 1.85 times on the 5
th
day (p < 0.05) compared with the value before administration.
Conclusion: mannitol 20% administration for acute stroke patients with increased intracranial
pressure showed increasing of serum ureum-creatinin level significantly.(p<0.05)
Keywords: Ureum-creatinin, acute stroke, mannitol


Abstrak: Latar belakang dan Tujuan: manitol digunakan secara luas untuk menurunkan tekanan
intrakranial dan pengurangan efek desak ruang dari perdarahan intraserebral. Ada beberapa
komplikasi dari penggunaan manitol berupa gangguan elektrolit dan cairan, edema kardiopulmoner.
Manitol bisa juga menyebabkan gagal ginjal dalam dosis terapi. Tujuan dari penelitian ini adalah
untuk mengetahui keamanan fungsi ginjal terhadap penggunaan manitol pada penderita stroke akut.
Bahan dan cara: penelitian ini bersifat interventional dengan metode pengumpulan data secara
prosfektif study terhadap seluruh penderita stroke akut dengan peninggian tekanan intrakranial di
ruang rawat inap neurologi Rumah Sakit Umum Pusat H.Adam Malik Medan periode 2 Januari 30
April 2005. Diberikan manitol 20% selama 5 hari. Dilakukan pengukuran nilai ureum-kreatinin serum
sebelum pemberian, pada hari ke-2, dan ke-5 sesudah pemberian manitol. Hasil: dari 25 penderita
(16 pria, 9 wanita), 9 penderita dengan stroke iskemik akut dan 16 dengan stroke hemoragik akut.
Selama pemberian manitol ditemukan peningkatan nilai ureum serum 1,40 kali pada hari ke-2
(p<0,05) dan 2,01 kali pada hari ke-5 (p<0,05). Nilai kreatinin serum meningkat 1,32 kali pada hari
ke-2 (p<0,05) dan 1,85 kali pada hari ke-5 dibandingkan dengan nilai sebelum pemberian manitol.
Kesimpulan: pemberian manitol 20% untuk penderita stroke akut dengan peninggian intrakranial
menunjukkan peningkatan nilai ureum kreatinin serum secara signifikan (p<0,05).
Kata kunci: ureum-kreatinin, stroke akut, manitol


INTRODUCTIONS
In Indonesia according to Family Health
Survey on 1995, stroke was one of the main
cause of mortality and disability which has to be
treated, immediately and accurately.
1

Many factors influence the out come of
stroke patients. One of them is complication in
either acute phase or rehabilitation periods.
Complication can be serious, causing death.
Common cause of these in stroke patients,
Dalton Silaban dkk. Changes of Ureum-Creatinin Level



Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 403
cerebral edema, heart disease, and pulmonary
emboli dominate in the first week.
2
The most lethal complication of stroke is
brain edema after large ischemic and
hemorrhagic stroke. In stroke units, brain
edema, pulmonary embolism, and cardiac
abnormalities are the mayor causes of early
death.
2,3

Intra cerebral hemorrhages, wide infarct
with cerebral edema cause compression
structures on brain, increase intracranial
pressure and can cause herniation. For decrease
this effect cerebral edema therapy should begin
as soon as possible.
3

Brain edema begins to develop in the brain
tissues surrounding the hematoma within the
first several hours after intracranial hemorrhage.
A hematoma combined with brain edema
causes compression of the surrounding brain
structures and elevation of intracranial pressure.
4
Mannitol is used worldwide to treat acute
stroke patients, although its efficacy and safety
have not been proven by randomized trials, thus
mannitol usage in therapy still controversial.
Clinical observation could not prove the
beneficial effect of mannitol in ischemic or
hemorrhage stroke in humans.
5

Mannitol is widely used to decrease
intracranial pressure and to alleviate the space
occupying effect of the brain hematoma .
6

Mannitol is reported to decrease cerebral
edema, infarct size, and neurological deficit in
several experimental models of ischemic
stroke.
7

Numerous studies confirm the nephrotoxic
potential of mannitol especially in patients with
renal insufficiency, and also in patients with
craniocerebral trauma without previous kidney
failure. Pathogenesis of mannitol induced renal
failure is not established but may be associated
with renal vasoconstriction produced by high
concentration of mannitol.
8

The most common complications of
mannitol therapy are fluid and electrolyte
imbalances, cardiopulmonary edema, rebound
cerebral edema, and seldom hypersensitivity
reaction.
Mannitol can also cause renal failure even
in therapeutic doses.
3,6,7,8

How ever the influence of osmotherapy on
renal function in patients treated with mannitol
due to increased intracranial pressure was not so
far well decribed.
9

T. Dziedzic et al in 2000, performed
studied on 51 patients with intra cerebral
hemorrhage primer, all of the patients was
treated with mannitol 20 % (0.25-0.5)
mg/kg/every 4 hours and furosemide 10mg
every 8 hours, mannitol was given for no longer
than 5 days and analysis the influences ureum-
creatinin serum concentration before mannitol
administration compared with 2
-nd
days, 5
-th

days, and 14
-th
days.
The conclusion from that study was
increased ureum creatinin serum
concentration after mannitol therapy on 2
-nd

days and 5
-th
days.
9
The aim of this study was to determine the
influence of mannitol therapy on renal function
with evaluate changes of ureum-creatinine
serum level after mannitol therapy in acute
stroke patients.

METHODS AND MATERIAL
This study was performed in neurology
ward of RSUP H. Adam Malik Medan since
January 2
nd
2005 to April 30
th
2005, on all
acute stroke patients with raised intracranial
pressure who fullfiled the inclusion and
exclusion criteria. The inclusion criteria is all
the acute stroke patients who have been treated
with mannitol and exclusion criteria is stroke
patients who are contraindicated for mannitol
such as renal failure, cardiac failure, dehydrated,
diabetes mellitus, and acute stroke patients who
administrated nefrotoxic drugs ( include
antibiotic)
The research was an intervention of data
collecting through prospective study.
All the patients were checked up according
to standardized protocol in Department of
Neurology, Medical Faculty University of
Sumatera Utara Haji Adam Malik Hospital
Medan Indonesia.
These check-ups consisted of complete
urine-blood-feces test, glucose nuchter and 2
hours post prandial, lipid profile, ureum-
creatinin. Uric acid, electrolyte, and liver
function test, CT scan within 24 hours, thorax
photo, electrocardiography, and fluid balance.
If Glomerular Filtration Rate (GFR) is less
than 15 during a mannitol administration, the
patients is disqualified from research .
GFR is gotten from (140-age)X
weight/72Xserum creatinin. For Women
cratinin clearance X 0.85 .
10,11
Patients fulfilled inclusion criteria were
given mannitol according to protocol in
Department of Neurology, Medical Faculty
University of Sumatera Utara Haji Adam Malik
Hospital Medan Indonesi in doses 125 cc/6
hours/ IV in 30 minutes. Serum ureum-creatinin
is known before the administration, second and
fifth day after administration of mannitol.
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Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 404
All hypertension patients were given ACE
inhibitor Captopril.
Serum ureum-creatinin was measured using
Automatic analysis Hitachi 902 machine.
Mannitol was mannitol 20% Otsuka,s
production.
To asses the outcome, Barthel index and
Glasgow Outcome Scale were used.
Statistical for Windows version 10.5 use to
analyze the difference of mean of ureum-
creatinin level between before administration
and second and fifth day, we used Anova test
since the variance were that same and Multiple
Comparisons Post Hoc Tests. To analyze the
influence of age toward changes of serum
ureum-creatinin level Pearson Correlation test
were used. To analyze the influence of sex
toward changes of serum ureum-creatinin level
T-test were used.
To analyze the out come after mannitol
administration with Barthel index and Glasgow
Outcome Scale Wilcoxon Signed Ranks Test
were used. The level of significance was set at
p<0.05.
Normal adult ureum level: 10-20 mg /dl or
3.6-7.1 mmol/L (SI units). Normal adult
creatinin for woman: 0.5-11mg/dL or 44-94
(micro mol/L SI units), men 0.6-1.1 mg/dL.
11

RESULTS
From 82 acute stroke patients (47 ischemic
stroke, 35 hemorrhagic), we found that 25
patients were administered mannitol (9 ischemic
stroke, 16 hemorrhagic stroke).


Table 1.
Demographic and characteristics in 25 acute stroke patients after mannitol administration
Ischemic stroke Hemorrhage stroke
n =9 (36%) n=16 (64%)

Sex
- male 5(20%) 11(44%)
- female 4(16%) 5 (20%)

Age
- < 45 year 3(12%)
- 45-55 year 9(36%) 7(28%)
- > 55 year

BP
*
on admission 6(24%)
- Normal 1(4%) 1(4%)
- H
*
.mild 1(4%) 2(8%)
- H. moderate 4(16%) 3(12%)
- H. severe 1(4%) 4(16%)
- H. very severe 2(8%) 6(24%)

Hypertension
- No 1(4%) 1(4%)
- Yes 8(32%) 15(60%)

Glasgow Coma Scale
- 13-15
- 9-12 8(32%) 14(56)
- 8 1(4%) 2(8%)
Death
- yes 1(4%) 8(32%)
- no 7(28%) 9(36%)

Cause of death
- cerebral herniation 8(32%)
- respiratory failure 1(4%)
* BP=Blood pressure
* H=hypertension

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Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 405
THE CHANGES OF UREUM SERUM LEVEL IN ACUTE STROKE PATIENTS
0
20
40
60
80
100
120
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
ACUTE STROKE PATIENTS

U
R
E
U
M


S
E
R
U
M

L
E
V
E
L
day-0
day-2
day-5

Figure 1. Changes of ureum serum level in 25 acute stroke patients on day-0, day-2 and day-5


THE CHANGES OF CREATININ SERUM LEVEL IN STROKE ACUTE PATIENTS
0
0.5
1
1.5
2
2.5
3
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
ACUTE STROKE PATIENTS
C
R
E
A
T
I
N
I
N

S
E
R
U
M

L
E
V
E
L
day-0
day-2
day-5

Figure 2. Changes of creatinin serum level in 25 stroke acut patients on day-0, day-2 and day-5


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Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 406
Most of the patients were male 16(64%) .
Mean age of patients was 57,84 year (3876),
with the most age group 45-55 years 16 (64%).
Patients with hypertension at admission were
found 23 (92%) and most of them had
hemorrhagic stroke 15(60%). All patients who
were admitted had loss of consciousness, 22
(88%) patients had Glasgow Coma Scale (GCS)
score 9-11. Of 25 patients, 9 (36%) patients died
and most of them, 8 (88%) had hemorrhagic
stroke. Mostly, the cause of death were cerebral
herniation 8 (88%) and respiratory failure was
1(12%) patients.
Mean serum ureum concentration was 33,5
11,3 mg % before mannitol administration
and increased to 46,8 13,4 mg% on the
second day and 67,6 18,0 mg % on the fifth
day after mannitol administration.
Mean score of serum creatinin was 0.90
0.23 mg % before mannitol administration and
increased to 1.19 0.36 in second day and
1.67 0,48 mg% in the fifth day after mannitol
administration.

After statistical analysis was done there was
a significant elevation in serum ureum
concentration before mannitol administration
than on the second day (p<0.05) and on the fifth
day (p<0.05) after mannitol administration. Serum
ureum level elevated for 1,4 times on the second
day (p<0.05) and 2,01 times on the fifth day
(p<0.05) (Figure 1).
Statistical analysis showed a significant
increased between creatinin concentration
before and after administration mannitol in the
second and in the fifth day (p<0.05)
Serum creatinin level increased in to 1.32
times on the second day and 1.85 times on the
fifth day (p< 0.05) compare with before
mannitol administration.(figure -2)
There was any correlation between age and
changes serum ureum-creatinin level on second
day and fifth day after mannitol administration (
p>0.05)
There was no correlation between sex and
changes of serum ureum-creatinin level on the
second and fifth day after mannitol
administration ( p>0.05).
Barthel index assessed on day-0 overall is
25 (100%) on 7
-th
day, 22 (88%) bad and 3 died
(12%). Where as on 14
-th
day Barthel Index bad
13 (59%), moderate 3 (13%) and died was 6
(28%).
Glasgow Outcome Scale assessed on 14
-th

day was death 9(36%), severe disability 13
(52%) and moderate disability 3 (12%).
There were no significant change in Barthel
index Score and Glasgow Outcome Scale
(p>0.05).
Table 3 shows that GFR before mannitol
administration to the patients were 5 at stadium1
9(20%), 12 at stadium2 (48%) and 8 were at
stadium3 (32%) after administering mannitol on
the second day, stadium3 increased to 18(72%) and
on fifth day, at stadium3 became 19 of them (76%)
and infarct 3 patients were found of stadium4.

Table 2.
Barthel Index value and glasgow outcome scale in 25 acute stroke patients
day-0 day-7 day-14
n( %) n(%) n(%)
Barthel index
- bad 25(100) 22(88) 13(52)
- moderate 3(12)
- excellent
Glasgow Outcome scale
- death 9(36)
- severe disability 13(52)
- moderate disability 3(12)


Table 3.
Renal disease stadium according to GFR in 25 acute stroke patients
Stadium 1
*
Stadium 2 Stadium 3 Stadium 4 Stadium 5
n (%) n (%) n (%) n (%) n (%)

Before treatment mannitol 5(20) 12(48) 8 (32)
2
-nd
day 4(16) 3(12) 18(72)
5
-th
day 2(8) 1(4) 19(76) 3(12)


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Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 407
Abbrevation GFR= Glomelural filtration Rate
Stadium 1= Renal impairment with normal GFR 90
Stadium 2 = mild impairment with GFR 60-90
Stadium 3 = moderate impairment GFR 30-59
Stadium 4 = severe impairment GFR 15-29
Stadium 5 = Renal failure GFR < 15
Abbrevation GFR = Glomelural filtration rate





DISCUSSION
There are two main categories in which
predisposition to renal damage is increased , firstly,
patients with impaired renal perfusion pressure due
to sodium depletion, diuretic therapy, low cardiac
output or any other condition that tends to promote
increased sodium reabsorption and secondly,
patients with already impaired renal function,
vascular disease, severe infection diabetes mellitus
or liver disease .
12
From this study, 25 patients ( man 16, woman
9) aged 38-76 years (mean 57,4 10.0 years) with
acute stroke (9 ischemic stroke, 16 hemorrhagic
stroke), this number differ from previous study by
T. Dziedzic on 2000, where they found 51 patients
(29 man, 22 woman) aged 28-86 years (mean 64,6
12,7 years) with supratentorial intra cerebral
hemorrhagic.
9
The small sample in this study compared to
other previous studies is one of the limitation of
this study. In this study, samples were acute
ischemic and hemorrhage patients, while in
previous studies were only toward hemorrhage
stroke. Overall will shows different response on
mannitol administration as anti edema.
In this study there were 23(92%) hypertension
patients and the most were hemorrhage stroke
patients 15(60%). This is probably due to hidden
changes in kidney, in this case patients have a
tendency on having renal failure during therapy.
J.A Withwort reported analysis toward 83 patients
with accelerated hypertension, found underlying
cause (usually renal) for hypertension.
13
If operational definition of acute renal failure
is Glomerular Filtration Rate (GFR) is < 15, no
patient suffered from renal failure after mannitol
administration on the fifth day. But tendency
toward that was present, where 3(12%) patients
with severe GFR reduction (stadium4) and
19(76%) with moderate GFR reduction (stadium 3)
see table-4.
Although serum ureum-creatinin
concentration increased during mannitol
administration, during therapy no patients with
oliguria or anuria was present.
T.Dziedzic et al found 76% of 51heorrhage
stroke patients suffered from renal failure after
mannitol 20% administration on the fifth day.
Meanwhile, Dorman HR found 8 cases of acute
renal failure induced by mannitol administration
for more than 3.5 1,5 days.
9
During mannitol administration, serum ureum
level increased 1,4 times on the second day ( p<
0.05) and 2.01 times on the fifth day (p<
0.05).Serum creatinin level increased 1.32 times
on the second day (p< 0.05) and 1.85 times on the
fifth day (p< 0.05) . These finding were similar to
the finding by T. Dziedzic on 2000, where they
found serum ureum level increase 1.5 times on the
second day (p = 0.0001) and 2.3 times on the 5
fifth day (p= 0.00001) while serum creatinin level
1,2 times on the second day (p = 10
-5
) and 1.3
times on the fifth day (p = 10
-5
). It shows that
mannitol administration during therapy caused
increasing of serum ureum- creatinin level .
All patients were admitted with
unconsciously. Twenty two (88%) had Glasgow
Coma Scale of 9-12 and 2(12%) had Glasgow
Coma Scale <8. During mannitol therapy, 9(36%)
patients died. This is similar to previous study by T.
Dziedzic that found 20(39%) patients died from 51
patients who were given mannitol. Considering the
high mortality with the most caused by cerebral
herniation 8(88%). We questioned whether
mannitol was useful in decreasing intracranial
pressure by reducing mid line shift.
A Glasgow Coma Scale score of less than 8, a
wide pulse pressure, a large hemorrhage, and intra
ventricular extension indicate poor prognosis.
14
E.M. Manno et al did a study to investigated
the effect of mannitol administration on cerebral
edema after large infarct on cerebral hemisphere,
from 7 patients it,s concluded that mannitol
administration didn,t change midline tissue shift or
neorological deficit worsening (effect of
mannitol).
15
We assessed the out come using Barthel index
on the admission day, the seventh day and
fourteenth day and Glasgow Outcome Scale on the
seventh day and fourteenth day.
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Majalah Kedokteran Nusantara Volume 39 No. 4 Desember 2006 408
Barthel index score on the fourteenth days was
still bad (0-65) on 13 (59%) patients and moderate
(60-90) on 3(13%), While Glasgow Outcome Scale
on the fourteenth day was death 9(36%) , severe
disability 13(52%) and moderate disability 3(13%).
This score is probably due to the early scoring
of outcome for 2 weeks after onset. This score
could be change if the scoring was done 3 months
later.

CONCLUSIONS
1. There is a significant change in serum ureum-
creatinin level after mannitol 20%
administration.
2. There are no correlation between age , sex and
serum ureum-creatinin level after mannitol
administration.
3. There are no significant change in Barthel
index Score and Glasgow Outcome Scale.

COMMENT
1. Mannitol administration to the acute stroke
patients should be carefully especially to the
hypertension and diabetes mellitus patients
2. During mannitol administration we should
check renal function as control.
3. We need further studies with a larger sample.


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