KakucsC_Drotaverinum


 

 

 

 

 
Romanian Neurosurgery (2016) XXX 2: 177-183 | 177 

 

 

 

 

 

 

 

Drotaverinum – a new modality of prevention and 

treatment in cerebral vasospasm after subarachoidian 

hemorrhage? 

C. Kakucs1,2, C. Berce3, A. Tamas-Szora4, G. Ungureanu2,   

I.St. Florian2,5 

1PhD student, University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania, 

Neurosurgical Department; 2Cluj County Clinical Emergency Hospital, Neurosurgical 

Department; 3University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania, 

Laboratory Animal Facility; 4University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj-

Napoca, Romania, Human Anatomy and Embriology Department; 5University of Medicine and 

Pharmacy “Iuliu Hatieganu” Cluj-Napoca, Romania, Neurosurgical Department 

 
Abstract: Aim: This study want to demonstrate the efficaciousness of drotaverinum as a 

replacer of papaverine in the prevention and treatment of vasospasm. Material and 

method: In this study were used 20 albino Wistar male rats. Rats were divided in two 

groups and vasospasm was induced to the both femoral artery and after that irrigation 

of the femoral arteries with drotaverinum was performed to demonstrate the 

vasodilatation that can appear (group A). In the group B after the obtaining of vasospasm 

irrigation of the femoral arteries with saline solution was performed and this group was 

used as witness. The length of the vessels was measured when was achieved the 

vasospasm and also before and after the administration of the solutions. Pictures were 

taken at every step of dissection and solutions administration to can measure the length 

of arteries before and after the administration of drotaverinum and the saline solution. 

Results: In all rats was obtained vasospasm at the femoral artery after clipping the artery 

and after we irrigate with adrenaline. In the group with drotaverinum we obtained the 

vasodilatation and in the witness group the caliber of the vessels remain the same. The 

statistical analysis of the data demonstrate a significant differences between the group 

were was used drotaverinum and the witness group were was used the saline solution 

(p<0,001). Conclusions: Drotaverinum has a good vasodilatative effect on arteries and he 

can prevent the apparition of vasospasm and it can even treat vasospasm if occur by 

producing local vasodilatation and a good circulation in the area where is administrated. 

This study showed quantitatively that drotaverinum can treat the experimental 

peripheral vasospasm in rats. 

Key words: vasospasm, drotaverinum, experimental study 

 



 

 

 

 

 
178 | Kakucs et al - Drotaverinum – prevention and treatment in cerebral vasospasm 

 

 

 

 

 

 

 

Introduction 

Cerebral vasospasm can occur after 

subarachnoidian hemorrhage and is one of the 

leading causes of morbidity and mortality in 

this type of pathology (1-3). Subarachnoidian 

hemorrhage represent the bleeding in the 

subarachnoidian space and the most frequent 

pathology that can determine that bleeding are 

the ruptured aneurysms (4). 

Cerebral vasospasm after subarachnoidian 

hemorrhage represent a challenge problem 

from the prevention and treatment point of 

view and contributes to the most devastating 

injury: delayed cerebral ischemia (2, 5, 6). 

When delayed cerebral ischemia occur the 

patient outcome is poor and this can lead even 

to death (6). 

The objective of our study was to 

demonstrate on rats models the benefits of 

drotaverinum when is applied on a spastic 

artery and to demonstrate the efficacy instead 

of papaverine. Also intraoperatory cisternal 

irrigation with drotaverinum of the arteries 

after the aneurysm is clipped is performed to 

prevent the apparition of the vasospasm or 

even to treat this if already has developed.  In 

our statistics the incidence of cerebral 

vasospasm is lower than the data from the 

literature and we thought that is happening 

because of the use of drotaverinum. 

In the literature are studies about cisternal 

irrigation after clipping the aneurysm but with 

papaverine not with drotaverine (7). In 

literature are studies about the resistance 

against intra-arterial papaverine in cerebral 

vasospasm or about the efficacy of papaverine 

in this type of pathology but about 

drotaverinum there’s no study to see if is a good 

option to use it instead of papaverine (8, 9). 

Materials and methods 

Animals and housing  

Twenty (n=20) male HsdOla:WI rats 

weighing between 300 and 350 grams were 

used in the present study. The animals were 

housed in polysulfone type III open-top cages 

(Tecniplast, Italy) and had access to filtered tap 

water in bottles and peletted feed (Nutret 

combinat granulat, Cantacuzino Institute, 

Romania) ad libitum. The rats were kept in the 

Laboratory Animal Facility of the „Iuliu 

Hatieganu” University of Medicine and 

Pharmacy at a standard temperature of 24 ± 2 

°C, a relative humidity of 55 ± 10%, 12:12-h 

light:dark cycle (lights on, 0700 to 1900). All 

experimental protocols were approved by the 

Ethics Comittee of the University (no. 

301/29.05.2015 ) and were conducted in 

accordance the EU Directive 63/2010, as per 

which, the experimental procedure severity 

was classified as moderate, as the animals fully 

recovered and were not sacrificed after the 

procedure. 

Experimental procedure 

The animals were randomly assigned into 

two (n=2) groups of ten (n=10) individuals per 

group. Group A was used to assess the 

efficiency of drotaverinum for preventing the 

occurrence of vasospasm, while group B was 

used as a control group. The rats were 

anesthetized by a intramuscular injection of a 

Xylazine:Ketamine cocktail in a dosage of 8 

mg/kg Xylazine to 80 mg/kg Ketamine. After 



 

 

 

 

 
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anesthesia, the animals were positioned in a 

dorsal decubitus. 

After positioning the rats was performed 

shaving the medial part of the posterior legs 

and was make a skin incision about 2 cm and 

dissect the anatomical structures till was 

discovered the femoral artery and of course the 

femoral vein and sciatic nerve in the medial 

and respectively lateral side of artery. The 

dissection was continued till the femoral artery 

was isolated (figure 1). After the preparation of 

the femoral artery a vascular clip was put 

(figure 2) and maintained it for 2 minutes and 

at the same time the artery was irrigated with 

adrenaline (0,1 ml with concentration of 

1/1000). After 2 minutes the clip was removed 

and the narrowing of the lumens artery was 

obtained (figure 3). When the experimental 

vasospasm was obtained the irrigation of the 

femoral artery with drotaverinum (0,1 ml) was 

performed and after another 2 minutes the 

vessel was dilated (figure 4). This protocol was 

applied for all the 10 animal models from the 

group A and the experiment was made on the 

both posterior legs. 

In the witness group was used the same 

protocol as was mentioned above with the 

exception that the irrigation of the femoral 

artery, after the experimental vasospasm, was 

made with saline solution not with 

drotaverinum. In this group was observed that 

the saline solution does not produce 

vasodilatation and the vessels remains 

narrowed were was put the vascular clip. 

The dissections were performed with 

microsurgical instruments under the 

microscope (Leika). Each step of the study 

protocol with the femoral artery was 

photographed. After finishing the study 

measurements on arteries after clipping, after 

tamponing with drotaverinum and with saline 

solution was achieved. The measurements 

were performed with a special soft of 

morphometry (Axiovision Rel 4.6.) (figures 5 

and 6). 

After the experimental study the animal 

models were observed till 7 days to see if they 

develop some complications after the 

vasospasm that was induced. In group A 

doesn’t occur any complication due to 

vasospasm, but in the group B occurred 2 

posterior limb ischemia that maybe was 

produced by the narrowing of the femural 

artery. 

The statistical analysis was performed 

using MedCalc soft. The statistical tests which 

were applied were T-test and correlation 

coefficient that will be shown in the results. 
 

 
Figure 1 - Femoral artery of the right posterior limb 

and its relationship with the sciatic and femoral vein 

 



 

 

 

 

 
180 | Kakucs et al - Drotaverinum – prevention and treatment in cerebral vasospasm 

 

 

 

 

 

 

 

 
Figure 2 - The vascular clip on the femoral artery 

 

 
Figure 3 - We can observe the experimental 

vasospasm obtained on femoral artery that appeared 

after clipping and irrigate the artery with adrenaline 

 
Figure 4 - The dilated artery after the irrigation with 

drotaverinum 

 

 
Figure 5 - Measurement of the femoral artery after 

clipping and irrigation with adrenaline 

 



 

 

 

 

 
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Figure 6 - Measurement of the femoral artery after 

irrigation with drotaverinum 

 

 
Graph no.1 The diameter of the vessel is depicted 

before and after the irrigation of the arteries with 

drotaverinum 

 

 
Figure 7 - Data platted for group A and B. Error bars drown at the 95% confidence interval. Red points 

representing the means 

 

Results 

After the dissections and the 

measurements that were performed on the 

femoral arteries we analyzed all the data using 

MedCalc soft. 

The first statistical tests was applied to see 

if there is a significant difference between 

group A were was used the drotaverinum and 

the group B were was not administrated the 

drotaverinum. After the statistical analysis we 

obtained a significant difference between the 

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

ratio post inainte toate NOSPA ratio post inainte toate MARTOR



 

 

 

 

 
182 | Kakucs et al - Drotaverinum – prevention and treatment in cerebral vasospasm 

 

 

 

 

 

 

 

two groups with p<0,0001 and that suggest the 

benefits of the irrigation with drotaverinum 

when  vasospasm is occurred. 

In Graph no.1 the diameter of the vessel is 

depicted before and after the irrigation of the 

arteries with drotaverinum. The mean of the 

vessels before irrigation with drotaverinum 

was 37,66 and after the administration of 

drotaverinum the mean was 56,97. The 

statistical analysis depicted a significant 

difference between the two means (p<0,05). 

Statistical tests in the group B were applied 

before and after the irrigation with saline 

solution. The mean before irrigation was 45,44 

and after irrigation with saline solution the 

mean was 44,23. In this group we observe the 

saline solution has no effect on the vessels. 

Between the two groups there was no 

differences in the diameter of the vessels 

before the irrigation with drotaverinum or 

with the saline solution and the standard 

deviation was 7,83±1,75. 

After the irrigation with drotaverinum in 

the group A and the irrigation with saline 

solution the group B the mean of the vessels 

diameter in the first group was 52,02 and in the 

group B the mean was 44,23. The statistical 

analysis depicted a significant difference 

between the two means (p<0,001). 

All the data were analyzed and we obtained 

a statistically significant difference between 

the two groups after the irrigation with 

drotaverinum (p<0,001) with a standard 

deviation 13,76±3,07. 

In figure 7 we can see the data platted for 

group A and B. The red points represent the 

means. p<0.001. 

Discussion 

Cerebral vasospasm is a difficult 

pathological entity to treat or to deal with it 

and also in the literature are a lot of studies and 

trials about the controversies concerning the 

prevention and the treatment of the cerebral 

vasospasm that can occur after 

subarachnoidian hemorrhage (10-13).   

Cerebral vasospasm after subarahnoidian 

hemorrhage produced by ruptured aneurysms 

remains still a very controversial topic (14). 

Cerebral vasospasm represent the leading cause 

of mortality and morbidity in subarachnoidian 

hemorrhage and can lead to delayed cerebral 

ischemia (1, 2). In the treatment of cerebral 

vasospasm the only medication that was proven 

to reduce delayed cerebral ischemia is the 

nimodinipine (1, 15-17). 

About 30% of patients who suffered 

nontraumatic subarachnoidian hemorrhage 

develop cerebral vasospasm and secondary to 

this they develop ischemia (10). Cerebral 

vasospasm occur often in the third day after 

the hemorrhage and in the day 5 to 7 riches the 

maximum (11). 

In the treatment of cerebral vasospasm are 

included the triple H therapy (hypertension, 

hypervolemia, hemodilution), balloon 

angioplasty, intra-arterial vasodilatators, 

administration of substances like statins, 

endothelina-1 antagonists and magnesium 

sulfate (2, 5, 11). 

Conclusions 

Our study demonstrate the importance of 

using the drotaverinum after the vasospasm 

occurrence and is very important to perform 



 

 

 

 

 
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irrigation with drotaverinum on the cerebral 

arteries after clipping the aneurysm because 

this will prevent the occurrence of  vasospasm 

or will treat it if occurred. 

Drotaverinum has no complication if we 

use it to irrigate the cerebral arteries and the 

vasodilatation that appears after using 

drotaverinum is useful because is achieved a 

better blood circulation in the area and 

prevent the ischemia occurrence. 

In our opinion after the aneurysm is 

clipped the irrigation of the vessels, 

surrounding the aneurysm, with 

drotaverinum can decrease the incidence of 

vasospasm. Also if, intraoperative, we find a 

visible vasospasm the irrigation of the arteries 

with drotaverinum will help the vessel to dilate 

and to return to optimal caliber for the blood 

flow. 

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