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The effect of piracetam on brain damage and serum nitric oxide levels in dogs
submitted to hemorrhagic shock

Article  in  Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery: TJTES · November 2008
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Turkish Journal of Trauma & Emergency Surgery Ulus Travma Acil Cerrahi Derg 2008;14(4):277-283
Experimental Study Deneysel Çal›flma

The effect of piracetam on brain damage and serum

nitric oxide levels in dogs submitted to hemorrhagic shock

Hemorajik flok oluflturulan köpeklerde beyin hasar› ve serum nitrik oksit

seviyelerine pirasetam›n etkisi
1 1 2
Seda ÖZKAN, ‹brahim ‹K‹ZCEL‹, Erdo¤an Mütevelli SÖZÜER,
Levent AVfiARO⁄ULLARI,1 Figen ÖZTÜRK,3 Sebahattin MUHTARO⁄LU,4
Okhan AKDUR,1 Can KÜÇÜK,2 Polat DURUKAN1

BACKGROUND AMAÇ
To demonstrate the effect of piracetam on changes in brain tis- Hemorajik flok oluflturulan köpeklerde, pirasetam›n floka ba¤-
sue and serum nitric oxide levels in dogs submitted to hemor- l› nitrik oksit düzeylerinde de¤iflikli¤e ve beyin dokusunda
rhagic shock. oluflan hipoksiye etkisinin olup olmad›¤› araflt›r›ld›.
METHODS GEREÇ VE YÖNTEM
The subjects were randomized into four subgroups each con- Denekler randomize olarak 10’ar köpekten oluflan dört gruba
sisting of 10 dogs. Hemorrhagic shock was induced in Group ayr›ld›. Grup I, bir saatlik hemorajik floka u¤rat›ld› ve hemora-
I for 1 hour and no treatment was given to this group. Blood jik flok sonras› tedavi verilmedi. Grup II, bir saatlik hemorajik
and saline solutions were administered to Group II following floka u¤rat›ld› ve flok sonras› kan ile birlikte serum fizyolojik
1 hour hemorrhagic shock. Blood and piracetam were given to verildi. Grup III, bir saat hemorajik floka u¤rat›ld› ve flok son-
Group III following 1 hour shock. No shock was induced and ras› kan ile birlikte intravenöz pirasetam verildi. Grup IV’e ise
no treatment was applied to Group IV. Blood samples were flok ve tedavi uygulanmad›. Deneyin bafllang›c›nda, 60., 120.
obtained at the onset of the experiment and at 60, 120 and 180 ve 180. dakikalarda nitrik oksit analizi için kan örnekleri
minutes for nitric oxide analysis. For histopathological exami- al›nd›. Deneyin sonunda, histopatolojik inceleme için beyin
nation, brain tissue samples were obtained at the end of the doku örnekleri ç›kar›ld›.
experiment. BULGULAR
RESULTS Kan bas›nc› ve nab›z de¤erlerindeki düzelmenin Grup III’deki
The observed improvement in blood pressure and pulse rates deneklerde Grup II’deki deneklere göre daha iyi oldu¤u sap-
in Group III was more than in Group II. Nitric oxide levels tand›. Grup I’de nitrik oksit seviyelerinde yükselme olmas›na
were increased in Group I; however, no correlation between ra¤men, pirasetamla nitrik oksit seviyeleri aras›nda herhangi
piracetam and nitric oxide levels was determined. It was seen bir iliflki saptanmad›. Deneyin sonunda, Grup III’de hemora-
that recovery in brain damage in Group III was greater than in jik floka ba¤l› geliflen beyin hasar›ndaki düzelmenin kontrol
the control group. grubuna göre daha iyi oldu¤u saptand›.
CONCLUSION SONUÇ
Piracetam, added to the treatment, may decrease ischemic Tedaviye eklenen pirasetam hemorajik flokta iskemik hasar›
damage in hemorrhagic shock. azaltabilir.
Key Words: Brain damage; dogs; experimental model; hemorrhagic; Anahtar Sözcükler: Beyin hasar›; köpek; deneysel model; hemorajik;
nitric oxide; piracetam; shock; treatment. nitrik oksit; pirasetam; flok; tedavi.

Departments of 1Emergency Medicine, 2General Surgery, 3Pathology, and Erciyes Üniversitesi T›p Fakültesi, 1Acil T›p Anabilim Dal›,
4
Biochemistry, Medicine Faculty of Erciyes University, 2
Genel Cerrahi Anabilim Dal›, 3Patoloji Anabilim Dal›,
4
Kayseri, Turkey. Biyokimya Anabilim Dal›, Kayseri.
Presented at the 3rd Mediterranean Emergency Medicine Congress 3. Akdeniz Acil T›p Kongresi’nde poster bildirisi olarak sunulmufltur
(September 1-5, 2005, Nice, France). (1-5 Eylül 2005, Nice, Fransa).

Correspondence (‹letiflim): Seda Özkan, M.D. Erciyes Üniversitesi T›p Fakültesi, Acil T›p Anabilim Dal›, 38039 Kayseri, Turkey.
Tel: +090 - 352 - 437 49 37 / 22331 Fax (Faks): +090 - 352 - 437 52 73 e-mail (e-posta): [email protected]

277
 Ulus Travma Acil Cerrahi Derg

Decrease in blood flow to the brain in hemor- were managed to spontaneous respiration without
rhagic shock, depending on the type and duration of intubation. Surgical sterilization procedures were
ischemic event, can cause metabolic and cellular followed during the experiment. Two polyethylene
changes. The most common changes are brain catheters with diameters of 3 mm were placed in
edema, apoptosis, necrosis and disturbance of both vessel lumens after determining femoral arter-
blood-brain barrier.[1] ies and veins of the subjects. A three-way shunt was
Shock is a physiopathological condition in placed at the tip of the catheter. One tip of the triple
which circulation is inadequate to maintain tissue shunt placed in the artery was connected to the
perfusion and is unable to meet the oxygen monitor for continuous measurement of arterial
demand.[2] Increased production of free oxygen rad- pressure via pressure transducer during the experi-
icals due to ischemia in hemorrhagic shock and ment. The other routes were used to maintain hem-
nitric oxide (NO) play an important role in the orrhage in dogs and collect blood samples for NO
pathophysiology of hemorrhagic shock. Serum NO analysis. Blood, saline and piracetam were admin-
level decreases and therefore cellular damage istered through the catheter placed into the vein.
occurs.[3,4] According to modified Wiggers technique, via
Piracetam is the first clinically used nootropic catheter placed in artery, bleeding was maintained
agent. Its cytoprotective, antihypoxic, antioxidant by 50 cc/min hemorrhage rate until 40 mmHg mean
and microcirculation protective effects were proven arterial pressure was achieved in subjects exposed
in some studies.[5] With both central and peripheral to shock. During exposure to shock, in order to
effects, it decreases thrombocyte aggregation and maintain 40 mmHg mean arterial pressure, re-hem-
morphologic erythrocyte anomalies, and improves orrhage or redistribution of withdrawn blood was
peripheric microcirculation.[6] applied to subjects. Following hemorrhage, blood
withdrawn from subjects was preserved in phle-
Blood and fluid resuscitation is performed in the botomy bags at room temperature until redistribu-
treatment of hemorrhagic shock in emergency tion.
departments. Blood is the best resuscitative fluid in
the treatment of hemorrhagic shock.[7] The subjects were randomized into 4 subgroups
consisting of 10 dogs each:
We aimed to investigate whether administration
of piracetam, with its proven cytoprotective and Shock group (Group I, n=10)
antioxidant properties, as an add-on therapy to early The subjects were exposed to shock for 1 hour
blood replacement in hemorrhagic shock is effec- and no treatment was given after shock.
tive on brain tissue damage and serum NO levels.
Control group (Group II, n=10)
MATERIALS AND METHODS Subjects were perfused with their withdrawn
This experimental study was performed in blood and placebo 4 cc/kg saline I.V. following 1-
Erciyes University Faculty of Medicine, Hakan hour shock.
Cetinsaya Experimental and Clinic Research Piracetam treatment group (Group III, n=10)
Center (DEKAM), E m e rg e n c y Department,
Biochemistry and Pathology Laboratory, with the Subjects were perfused with their withdrawn
permission of the Ethics Board, and it was support- blood and 4 cc/kg (800 mg/kg) piracetam
ed by Erciyes University Research Fund (Project (Nootropil®, UCB) I.V. bolus infusion following 1-
no: TT-03-17). Forty male Mongrel dogs weighing hour shock.
17 to 32 kg were used in the study. Before the Sham group (Group IV, n=10)
experiment, dogs were fasted for 12 hours. General
No shock or treatment was applied to the sub-
anesthesia was applied to all groups. Anesthesia
jects. However, other attempts were performed.
was maintained with intravenous (I.V.) 5 mg/kg
ketamine (Ketalar®, Pfizer) + 1 mg/kg xylazine For NO analysis, 10 cc blood samples were
hydrochloride (Rompun®, Bayer) by catheter obtained from the subjects at the outset of the
placed in the dogs’ left front leg vein. The subjects experiment and at 60, 120 and 180 minutes.

278 Ekim - October 2008

The effect of piracetam on brain damage and serum nitric oxide levels in dogs submitted to hemorrhagic shock

Table 1. Histopathologic evaluation of the brain variant analysis was used to compare the
Grade Findings histopathological results among groups. Mann-
Whitney U rank test was performed in the determi-
0 No injury nation of differences between groups. Values of
1 Mild injury, scarce necrotic cells (<10%) p<0.05 were considered as significant. Values were
2 Moderate injury, moderate necrotic cells (10-50%) expressed as mean ± SD.
3 Severe injury, many necrotic cells (>50%)
RESULTS
Blood pressure values
For histopathological analysis, at the end of the Median blood pressure was determined as 40
3rd hour, brain tissues were obtained from all sub- mmHg in the 15th minute of the experiment in all
jects by incision of cranium from temporal area. groups exposed to hemorrhagic shock. To achieve
All subjects were sacrificed by bleeding at the this blood pressure, test subjects were bled
end of the experiment. 852.2±119.6 cc. There was no difference between
the groups with respect to blood loss. Blood pres-
Lactate analysis sure was maintained at this value during shock.
Heparinized blood samples were taken from the Blood pressure values were increased in Groups II
subjects at the beginning of the experiment, and at and III in which hemorrhagic shock was treated. At
60, 120 and 180 minutes. These blood samples the end of the experiment, whereas a statistically
were analyzed by Rapid Lab 865 auto-analyzer significant difference was observed between
device in the emergency biochemistry laboratory. Groups II and IV (p<0.05), no differences were
Nitrite and nitrate analysis determined between Groups III and IV (p>0.05)
(Fig. 1).
Serum was isolated from blood samples taken
from dogs for analysis of nitrite and nitrate, and Pulse values
stored at -20 °C until the study day. As products of It was determined that pulse started to increase
the reaction between NO and oxygen, nitrite and at the 15th minute in all groups subjected to hemor-
nitrate levels were determined for permanent rhagic shock and was decreased in the treated
assessment of serum NO level. Nitrate/Nitrite groups. No statistically significant difference was
Calorimetric Measurement Kit (Calbiochem®) was observed between Groups II and III at the end of the
used for measurement. experiment (p>0.05). No significant difference was
Histopathological analysis found between Groups III and IV (p>0.05), where-
as a statistically significant difference was deter-
Brain tissue obtained for histopathological mined between Groups II and IV at the end of the
analysis was fixed in 10% formalin. All tissues experiment (p<0.05) (Fig. 2).
were embedded in paraffin following routine tissue
procedures, and paraffin sections of 5-8 microns
were prepared. 160
140
Preparations stained with hematoxylin-eosin 120 Group I
100
were observed under light microscope. 80
Group II

Histopathological grading recommendations by 60 Group III

40 Group IV
Warner et al.[8] were used to evaluate the histopatho- 20
logical changes (Table 1). 0
0 15 30 45 60 75 90 105 120 135 150 165 180
Statistical analysis Time (min)

All data were analyzed using the SPSS software Fig. 1. Blood pressure values among groups. (Median blood
pressure value was determined as 40 mmHg in the
package. One-way ANOVA test was used to com-
15th minute of the experiment in all groups exposed to
pare blood pressure, pulse, and serum nitrite and hemorrhagic shock. Blood pressure was maintained
nitrate levels among groups. Scheffe procedure was at this value during shock. In treated groups, blood
preferred in post hoc evaluation. Kruskal-Wallis pressure increased to the normal ranges).

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 Ulus Travma Acil Cerrahi Derg

Lactate values 160

140
Serum lactate levels were increased in hemor- 120
Group I
100
rhagic shock-applied groups and then decreased in 80 Group II
the treatment groups. There was no statistically sig- 60 Group III
Group IV
nificant difference between Groups II and III 40
20
(p>0.05). The difference between Groups II and IV 0
was statistically significant (p<0.05), whereas it 0 15 30 45 60 75 90 105 120 135 150 165 180
Time (min)
was not significant between Groups III and IV
(p>0.05) (Table 2). Fig. 2. Pulse rates of groups. (It was determined that pulse
started to increase at the 15th minute in all groups
Nitrite and nitrate values subjected to hemorrhagic shock and was decreased in
treated groups. In treated groups, pulse rate
A significant difference with respect to nitrite decreased to the normal ranges).
and nitrate values was determined among groups at
the 60th minute of the experiment. The differences
between Groups I and III and between Groups II Statistically significant differences between
and IV were statistically significant (p<0.05). Group I and Groups II, III and IV were determined
However, the differences between Groups II and III at the 120th minute and at the end of the experiment
and between Groups I and IV were not statistically (p<0.05). No significant differences between
significant (p>0.05) (Table 3). Groups II, III and IV were found (p>0.05).

Table 2. Lactate values among groups

Time (Min) Group I Group II Group III Group IV f p
X±SD X±SD X±SD X±SD
(mEq/L) (mEq/L) (mEq/L) (mEq/L)
0 1.9±0.6 2.7±1.3 2.9±1.0 1.9±0.5 3.3 >0.05
60 7.8±2.3d 7.8±1.5d 8.7±1.4d 2.3±1.1abc 31.2 <0.01
120 8.9±1.7bcd 5.2±1.7ad 4.3±0.9ad 1.7±0.4abc 49.8 <0.01
180 10.2±1.8bcd 3.9±1.2ad 2.6±0.5a 1.8±0.7ab 106.1 <0.01
*Values of p<0.05 were considered as significant; a: Demonstrates the difference compared to Group I;
b: Demonstrates the difference compared to Group II; c: Demonstrates the difference compared to Group III;
d: Demonstrates the difference compared to Group IV.

Table 3. Nitrite and nitrate values among groups

Time (Min) Group I Group II Group III Group IV f p
X±SD X±SD X±SD X±SD
(mEq/L) (mEq/L) (mEq/L) (mEq/L)
0 9.3±0.5 9.3±0.6 9.2±0.7 9.3±0.6 0.1 >0.05
60 9.4±0.9c 10.6±0.9 10.7±1.2ad 8.9±1.3c 6.2 <0.05
120 11.1±1.6bcd 9.6±0.5a 8.9±1.2a 9.1±0.5a 7.9 <0.01
180 14.4±1.2bcd 9.3±0.5a 8.4±0.4a 9.1±0.8a 129.9 <0.01
*Values of p<0.05 were considered as significant; a: Demonstrates the difference compared to Group I;
b: Demonstrates the difference compared to Group II; c: Demonstrates the difference compared to Group III;
d: Demonstrates the difference compared to Group IV.

Table 4. Histopathological evaluation of groups

Group I Group II Group III Group IV χ2 p
Median Median Median Median
(min-max) (min-max) (min-max) (min-max)
Brain 1 (0-2)cd 0 (0-2)d 0 (0-1)a 0 (0-0)ab 13.9 <0.05
*Values of p<0.05 were considered as significant; a: Demonstrates the difference compared to Group I;
b: Demonstrates the difference compared to Group II; c: Demonstrates the difference compared to Group III;
d : Demonstrates the difference compared to Group IV.

280 Ekim - October 2008

The effect of piracetam on brain damage and serum nitric oxide levels in dogs submitted to hemorrhagic shock

Table 5. Histopathological changes in brain tissue mean arterial blood pressures were decreased to 45
Grade 0 Grade I Grade II Grade III
mmHg at the 15th minute of the experiment and
pulse was increased. We also observed that blood
Group I 3 4 3 0 pressure was gradually increased and pulse was
Group II 6 2 2 0 decreased in treated groups II and III. In spite of the
Group III 9 1 0 0 statistically significant difference obtained between
Group IV 10 0 0 0 placebo and sham groups at the end of the experi-
ment, these values were in normal ranges for dogs.
No difference was observed between the piracetam-
Histopathological evaluation treated group and sham group.
Difference in brain tissue between Groups II and Some prognostic parameters show whether or
III was found statistically insignificant (p>0.05). not treatment of shock is appropriate. It was shown
No difference was found between Groups III and that the amount of oxygen shortage is a value to
IV (p>0.05), but there was a statistically significant determine the irreversible shock period.[14] Lactate
difference (p<0.05) between Groups II and IV has been used for a long time to evaluate the seve-
(Tables 4, 5, Figs. 3, 4). rity of shock.[15] In many studies, it was reported
that blood lactate level increased in hemorrhagic
DISCUSSION shock, and then decreased in treated groups; how-
Acute hemorrhage initiates specific cardiovas- ever, it was detected in some of these studies that it
cular, hormonal, and metabolic responses. Cardiac did not decrease to pre-treatment level.[11,13,16]
output is decreased in hemorrhagic shock and an In this study, at the end of the experiment, we
increase in peripheral vascular resistance occurs to determined a statistically significant difference
compensate for this decrease. Blood pressure has to between the group treated with blood and normal
be increased as long as this increase is maintained; saline and the sham group (p<0.05), but there was
however, it decreases because a sufficient compen- no statistically significant difference between the
sation mechanism cannot be achieved in the follow- sham group and group treated with blood and pirac-
ing stages.[9,10] etam (p>0.05). We observed that improvement in
It was shown with many experimental studies lactate level, which is an indicator of tissue perfu-
that blood pressure decreased and pulse rate sion, was better with the addition of piracetam to
increased during hemorrhagic shock and then shock treatment.
returned to normal with treatment.[11-13] In all groups Irreversible hemorrhagic shock is characterized
in which shock was applied, we determined that the by progressive vasodilatation related to loss of vas-

Fig. 3. Necrotic cells in brain tissue of a dog in Group II (H-E Fig. 4. Healing in the brain tissue of a dog after treatment in
x 400). Group III (H-E x 400).

Cilt - Vol. 14 Say› - No. 4 281

 Ulus Travma Acil Cerrahi Derg

cular reactivity in spite of sympathetic nervous sys- drawal of 30% of the total blood volume of anes-
tem activity. Insufficient vascular response to vaso- thetized rats. Loss of 35% of total blood volume
constrictor agents is found to be related to increased may lead to intermediate ischemia and loss of 50%
NO production and release. It is known that NO is of total blood volume leads to severe cerebral
derived from L arginine through the mediation of ischemia.[20] We also detected necrotic cells due to
nitric oxide synthesis (NOS) in vascular endothelial ischemia in the brain tissues of subjects exposed to
cells and causes permanent active vasodilatation.[3,17] hemorrhagic shock.
In two different hemorrhagic shock models per- In order to demonstrate piracetam’s cytoprotec-
formed with rats, NO levels were increased in irre- tive and apoptosis-preventing effect, Gabryel et
versible and untreated hemorrhagic shock.[17,18] al.[21] administrated piracetam to astrocyte cell cul-
Daughters et al.[19] established an increase in blood tures in vitro following hypoxia. As a result, it was
pressure by using NOS inhibitors in experimental shown that piracetam significantly reduced the
hemorrhagic shock. They reported that NO is amount of apoptosed cells.
increased in hemorrhagic shock and contributes to
In their experimental model, Grassler et al.[20]
hypotension.
looked for antihypoxic effects of piracetam in rats
Our results were similar to results of these stud- exposed to hypoxia by creating shock. They
ies. There was no difference between groups showed that piracetam prevented the changes after
according to NO levels. In the untreated group in hemorrhage in intermediate shock.
which hemorrhagic shock was induced, we deter-
In an experimental model performed with rats, it
mined no significant alteration at the 60th minute;
was found that 800 mg/kg intraperitoneally admin-
however, at and after the 120th minute, a significant
istered piracetam had neuroprotective eff e c t s
increase in NO values was observed. We observed
against hypoxia. When the rabbits were given 500
that the NO values were equal to their baseline in
mg/kg of piracetam I.V., the antihypoxic effect was
the treated groups.
found to be more significant than placebo.[22] We
Piracetam’s cytoprotective, antihypoxic, and administered high-dose piracetam (800 mg/kg) I.V.
microcirculation regulatory effects and its ability to to the subjects for its antihypoxic, antioxidant, cyto-
inhibit lipid peroxidation were demonstrated by protective and microcirculation protective effects.
several studies.[5] In an experimental study with rats
We also demonstrated in our study that necrotic
performed by Stockmans et al.,[6] it was demonstra-
cells were generated in brain tissue with intermedi-
ted that piracetam enhanced both central and
ate frequency after hemorrhagic shock and that this
peripheral microcirculation by reducing thrombo-
damage can be decreased by blood replacement.
cyte aggregation and erythrocyte deformability.
We also found that the brain damage occurring in
Because of these effects of piracetam, we pro- the piracetam-treatment group was less than in the
posed in our study to demonstrate whether it has an control group, though statistically insignificant. A
effect on NO in hemorrhagic shock. However, we statistically significant difference was observed
could not determine a correlation between pirac- between the control and sham groups, whereas no
etam and NO. The reason for this may be that NO statistical difference was determined between the
level increases in advanced stages of shock and we piracetam- treatment group and sham group.
treated the hemorrhagic shock state before the irre-
versible stage. In conclusion, the main treatment in hemorrhag-
ic shock is to stop bleeding and then replace blood.
According to some studies, brain edema, apop- However, when added to the blood replacement,
tosis, necrosis and disturbance of blood-brain barri- piracetam treatment may decrease the brain dam-
er due to ischemia were seen after hemorrhagic age. Piracetam has no positive or negative influence
shock.[1] Normal cerebral blood circulation can be on serum NO levels in hemorrhagic shock.
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