Minimally Invasive Therapy & Allied Technologies
ISSN: 1364-5706 (Print) 1365-2931 (Online) Journal homepage: http://www.tandfonline.com/loi/imit20
Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study Yigit Akin, Hakan Gulmez, Mutlu Ates, Erhan Ates & Mehmet Baykara To cite this article: Yigit Akin, Hakan Gulmez, Mutlu Ates, Erhan Ates & Mehmet Baykara (2015): Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study, Minimally Invasive Therapy & Allied Technologies To link to this article: http://dx.doi.org/10.3109/13645706.2015.1067627
Published online: 14 Jul 2015.
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Date: 27 September 2015, At: 03:55
Minimally Invasive Therapy. 2015; Early Online, 1–6
ORIGINAL ARTICLE
Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study
YIGIT AKIN1, HAKAN GULMEZ2, MUTLU ATES3, ERHAN ATES4, MEHMET BAYKARA5
Downloaded by [University of Tasmania] at 03:55 27 September 2015
1
Department of Urology, Harran University School of Medicine, Sanliurfa, Turkey, 2Department of Family Medicine, Duzce University School of Medicine, Duzce, Turkey, 3Department of Urology, Memorial Antalya Hospital, Antalya, Turkey, 4Department of Urology, Kahramanmaras State Hospital, Kahramanmaras, Turkey, and 5Department of Urology, Akdeniz University School of Medicine, Antalya, Turkey
Abstract Objective: To evaluate the effects of thiocolchicoside during endoscopic treatment of ureteral calculus. Material and methods: Between May 2014 and December 2014, 498 consecutive patients were enrolled. Exclusion criteria were operations under general anaesthesia, chancing laser lithotripter settings, and urinary tract infection. All patients were divided into three groups: Group 1 consisted of patients who were not administered thiocolchicoside, group 2 consisted of patients who were administered 5 mg thiocolchicoside, and group 3 consisted of patients who were administered 10 mg thiocolchicoside. Demographic, perioperative, and postoperative data were recorded. Complications were noted according to Clavien-Dindo classifications. A p value of p £ 0.05 was considered statistically significant. Results: A total of 427 patients (319 male and 108 female) with full data were investigated. Mean age was 43.3 ± 13.3 years. There were 157 patients in group 1, 141 patients in group 2, and 129 patients in group 3. Stone migration and operation time were significantly lower in groups 2 and 3 than in group 1 (respectively; p < 0.001, p = 0.03). However, usage of jj stents was significantly lower in group 3 than in the other groups (p < 0.001). Conclusion: Stone migration can be decreased by using locally administered thiocolchicoside in irrigation solution during endoscopic treatment of ureteral calculus. Additional doses may decrease usage of jj stents and operation time.
Key words: Endoscopic lithotripsy, holmium laser, skeletal muscle relaxants, ureteral calculi
Introduction Urinary stone disease is still a problem worldwide (1). The rate of urinary stones was recently concluded to be almost equal in both genders (1). Although diagnostic tools and treatment facilities have been developing, urinary stone disease requires manpower (2). Treatment options depend on stone type, place, and presence of metabolic disorders. The ureter is usually affected in the course of urinary stone disease. When the diameter of the ureter calculus is £5 mm, it is usually reduced spontaneously (1). If the ureter stone cannot be reduced spontaneously, endoscopic treatment options come into question (3). Ureteroscopy by semi-rigid ureterorenoscope and laser
lithotripsy is accepted as gold standard the for endoscopic treatment for ureteral calculus (1). However, ureteroscopy may not be easy to perform. Besides, the ureter calculus may migrate to the kidney due to irrigation and/or during fragmentation (4). Moreover, the ureter orifice may be tight and ureteral access may not be provided. Additional devices such as guide-wires and ureteral balloons are used for dilating the ureteral orifice. Additionally, if the patient is under general anaesthesia, a peripheral muscle relaxant may help us to access the ureter. At the end of these measures, the ureter may be damaged. Thus, clinicians may use jj stents. The ureteral calculus is now placed in the kidney and a simple endoscopic treatment procedure of ureteral calculi may become complex. At that time, the treatment
Correspondence: Y. Akin, Department of Urology, Harran University School of Medicine, 63100, Sanliurfa, Turkey, Fax: +90-414-318 3005, E-mail: [email protected] ISSN 1364-5706 print/ISSN 1365-2931 online 2015 Informa Healthcare DOI: 10.3109/13645706.2015.1067627
Downloaded by [University of Tasmania] at 03:55 27 September 2015
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Y. Akin et al.
procedure of urolithiasis may become a vicious circle for patients. To date, some devices have been presented for preventing ureteral calculi migration during ureteroscopy (5). The aim of ureteroscopy is to remove the stone and not to damage the ureter during the procedure. To date, no study has been published on locally administered drugs for preventing stone migration during uretroscopy. We investigated the effects of the central skeletal muscle relaxant drug thiocolchicoside during endoscopic treatment of ureteral calculus. Our hypothesis was that thiocolchicoside may relax the smooth muscles of the ureter, and thus lower the stone migration rate; usage of jj stents and ureteral dilatation balloon might be provided. This is the first clinical trial study in which thiocolchicoside was administered in irrigating solution of ureteroscopy during treatment of ureter calculus.
Material and methods We performed a retrospective analysis of prospectively recorded data. Patient data were recorded on a Microsoft Excel spreadsheet. The ethical committee approved the study and all patients signed consent forms. Exclusion criteria were operations under general anaesthesia, chancing laser lithotripter settings, and urinary tract infection. Indications for ureteroscopy and laser lithotripsy were accepted as defined in the guidelines of the European Association of Urology on urolithiasis (1). Between May 2014 and December 2014, 498 consecutive patients underwent endoscopic treatment or ureteral calculus.
Data collection Demographic data were collected including age (years), body mass index (BMI) kg/m2, American Society of Anaesthetists (ASA) score, comorbidities, urinary tract infection, diameter and location of ureter calculi, previous urinary stone disease, serum haemoglobin and creatinine, upper urinary tract dilatation in radiology evaluation (ultrasonography and/or non-enhanced computed tomography); perioperative data were collected including usage of thiocolchicoside, ureteral dilatation balloons, stone cone, stone migration, stone-free rate, amount of irrigation solution; postoperative data collected included complications and hospital stay. All complications were evaluated according to the Clavien-Dindo complication classification (6). Thiocolchicoside 5 mg and 10 mg were administered in the first irrigation solution varying among
groups during the operations. All patients were divided into three groups; group 1 consisted of patients who were not administered thiocolchicoside, group 2 consisted of patients who were administered 5 mg thiocolchicoside, and group 3 consisted of patients who were administered 10 mg thiocolchicoside.
Endoscopic ureter calculi treatment All patients received regional anaesthesia. Then, a 9.5f semi-rigid ureteroscope (Karl Storz, Tuttlingen, Germany) was used in the lithotomy position. A Holmium YAG laser (Elmed, Istanbul, Turkey) with a 5.5f laser probe was used for lithotripsy. The settings of the laser generator were 2.5 J with 5Hz in the 15 W. In general, only one irrigation was sufficient for the operation, as 3000cc 0.9% saline. Specifically, a guide-wire was used in male patients for accessing the ureter. A basket catheter was used for collecting fragmented calculus and a stone cone was used for reducing stone migration. In case of upper urinary tract dilatation, ureter damage during stone removal, stone migration, and slight stenosis in the orifice, jj stents were used. At the end of the operation, a 16f foley catheter was indwelled. All stone fragments were sent for analysis to the mine research institute of our community’s government (7). All patients were hospitalized for at least 24 hours after the operation. They were discharged on the first postoperative day after the catheter was removed. The jj stents were removed according to clinical follow-up after stone fragments were reduced or the upper urinary dilatation was decreased. Extra shock wave lithotripsy was performed when the stone could not be reduced. Stone fragments and nephroliths were followed-up by kidney ureter bladder x-ray and/or non-enhanced computed tomography in case of non-opaque calculi.
Statistical analyses We used the standard package in social research (SPSS) V16.0 for statistical analyses. The paired t tests were used for comparing variables. Significant p value was defined as p £ 0.05.
Results A total of 427 patients with full data were enrolled in the study. The mean age was 43.3 ± 13.3 years. There were 319 male and 108 female patients. The mean
3
Impact of thiocolchicoside on ureteral stone removal Table I. Demographic data of groups. Parameters
Group 1 (n = 157)
Group 2 (n = 141)
Group 3 (n = 129)
p value
Gender
35/122 (F/M)
30/111 (F/M)
33/96 (F/M)
0.68
ASA score
1.22 ± 0.41
1.20 ± 0.4
1.29 ± 0.52
0.17
Age (years)
41.9 ± 11.2
42.7 ± 11.9
43.3 ± 13.3
0.06
BMI (kg/m )
26.2 ± 3.9
26.6 ± 3.8
26.1 ± 4.1
0.5
UTI before operation
28
31
27
0.6
Comorbidities
51
40
37
0.6
Stone history
72
63
64
0.7
Previous operation
54
40
37
0.4
0.4
2
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Medical expulsive treatment No
26
17
16
NSAI
92
101
96
a-blocker
39
23
17
Lower
63
61
56
Medium
46
44
38
Upper
48
36
35
Grade 0
29
28
22
Grade 1
43
37
31
Grade 2
43
42
41
Grade 3
42
34
35
8.46 ± 3.06
7.69 ± 2.91
7.86 ± 3.33
Ureter calculi location 0.6
Upper urinary tract dilatation on site of ureter calculi
Stone size
0.7
0.7
Abbreviations: ASA: American Society of Anaesthesiologists, BMI: Body mass index, NSAI: Non-steroidal anti-inflammatory, UTI: Urinary tract infection.
body mass index was 26.3 ± 4.1 kg/m2. There were 157 patients in group 1, 141 patients in group 2, and 129 patients in group 3. There was no urinary tract infection before the operation. Besides, there were no statistical differences among groups, according to the demographic data (Table I). The location and mean size of ureteral calculi, rate of kidney dilatation at the site of the ureteral calculi, and usage of ureteral dilatation balloons were similar in all groups (Table I). Stone migration and operation time were significantly lower in groups 2 and 3 than in group 1 (respectively; p < 0.001, p = 0.03; Table II). However, usage of jj stents was significantly lower in group 3 than in the other groups (p < 0.001). However, hospital stay, postoperative complications, and stone analyses were similar among groups. These data are summarized in Table II. The most common postoperative complication was haematuria, and this was treated by intravenous hydration (Clavie-Dindo Class 1). Five patients in
group 1, two patients in group 2, and four patients in group 3 had postoperative fever due to urinary tract infection. They needed additional antibiotics (Clavien-Dindo Class 2). In total, 11 patients (six patients in group 1, four patients in group 2, and one patient in group 3) needed jj stents under local anaesthesia due to increased lumbar pain after the operation (Clavien-Dindo Class 3). The present series had no Clavien-Dindo class 4 and 5 complications.
Discussion The present study demonstrated a significant decrease in usage of jj stents and stone migration by locally administered moderate doses of thiocolchicoside (5/10 mg) during endoscopic treatment of ureteral calculi. Furthermore, these were associated with a significant decrease in operation time. Additionally, less urinary tract infections occurred after
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Y. Akin et al.
Table II. Perioperative and postoperative data of groups. Parameters
Group 1 (n = 157)
Group 2 (n = 141)
Group 3 (n = 129)
p value
Stone migration
16/141 (Yes/No)
7/134 (Yes/No)
4/125 (Yes/No)
0.03*
Operation time (min.)
43.6 ± 16.2
32.5 ± 14.4
27.6 ± 7.8
< 0.001*
Usage of jj stent
61
30
25
< 0.001*
Hospital stay
1.19 ± 0.52
1.11 ± 0.42
1.08 ± 0.34
0.07
Postoperative complications
13/144 (Yes/No)
6/135 (Yes/No)
4/125 (Yes/No)
0.1
Ca-oxalat
131
121
110
0.8
Struvit
17
15
13
Uric acid
9
5
6
Downloaded by [University of Tasmania] at 03:55 27 September 2015
Stone analyses
*Statistical significant p value.
ureteroscopy in group 3, in which 10 mg thiocolchicoside was used, than in other groups. As a result, usage of thiocolchicoside in irrigating solution (approximate rationale was 5 mg/3000 cc in group 2 and 10 mg/ 3000 cc in group 3) was beneficial during ureteroscopy for the treatment of ureter calculi. Moreover, we excluded patients who underwent ureteroscopy under general anesthesia because we wanted to eliminate any effects of other peripheral muscle relaxant drugs. Even though numerous devices and operation techniques have been described, according to our best knowledge no drug for reducing stone migration during ureteroscopy has been investigated to date (8–10). Stone cone is an endoscopic device that can reduce stone migration during ureteroscopy. Although stone migration can be managed by using this device, it is associated with considerable cost. Nevertheless, there is still a lack of drug-based studies in the published literature (11). This may be due to the fact that most peripheral muscle relaxant drugs are used via the parenteral route and side effects may be life-threating (12). Thicolchicoside is a central muscle relaxant and has been safely used by oral and parenteral route for years (13). Because it is a central muscle relaxant agent, it connects on gamma-aminobutyric (GABA) receptors as agonist (14). However, there are peripheral branches of the central nervous system around the ureter, and all receptors of GABA are located in these branches (15). Recently, Kertmen et al. reported muscle relaxant effects of thiocolchicoside on the vascular plain muscles of brain vessels in a rabbit model (14). They showed that thiocolchicoside affected the smooth muscles of vessels in the brain. We strongly think that the results of the present study can be interpreted along the same
line. Thiocolchicoside directly affects the peripheral branches of neurons and GABA receptors. Thiocolchicoside is a central muscle relaxant drug, and no paper has been published to date describing the rationale for using this drug on the ureter; the same holds true for preclinical in vitro studies on ureter muscle strips and characterization of the sensitive receptors, drug-binding features, pharmacokinetic data, electrophysiological cause-effect studies. It is a well-known truth that GABA receptors are affected by central muscle relaxant agents (13). We used the locally administered forms by adding these in moderate doses in the first irrigating solution of ureteroscopy. In the present study, our hypothesis was that when thiocolchicoside was induced in irrigating solution, it connects to its own GABA receptors of peripheral neurons related to the urothelial mucosa and the ureter. Thus, the smooth muscles of the ureter can relax in a mechanism similar to that published by Kertmen et al. (14). In this set-up, the possible mechanism consists of affecting its GABA receptors and thus chloride enters into neuron cells. This then leads to inhibit voltage-activated Ca2+ in the postsynaptic smooth muscles and in peripheral neuromuscular junctions. Thus, the smooth muscles of the ureter could relax. The present series can be seen as a proof of that mechanism. We did not meet any side effects of thiocolchicoside in the present series. It is known that the bioavailability of thiocolchicoside is as low as 25% (16). This can be overcome by using this in the irrigating solutions. Dose titration may come into question. Taken together, thiocolchicoside was effective in irrigation solution of ureteroscopy. However, more molecular studies are needed to describe the exact mechanism.
Downloaded by [University of Tasmania] at 03:55 27 September 2015
Impact of thiocolchicoside on ureteral stone removal The jj stents are widely used for the management of ureteral obstruction and to prevent complications after ureteroscopy; patient discomfort can come into question (17). High pressure transmitted to the renal pelvis, as well as trigonal irritation by the intravesical part of the stent, constitute some factors of irritation. Additionally, Deliveliotis et al. reported stent-related pain and urinary frequency (18). These symptoms continue until stent removal. On the other hand, Damiano et al. reported complications of jj stents such as bacteriuria, stent migration, and haematuria (19). In the present study we found that moderate doses of thiocolchicoside could reduce usage of jj stents. However, complications and discomfort can be reduced by using less jj stents during ureteroscopy; the exact molecular mechanism should be shown in future detailed studies. Tepeler et al. evaluated intraoperative complications of ureteroscopy by using the Satava classification (20). Stone migration was classified as a type 2 complication. According to our results, using intracorporeal thiocolchicoside significantly prevented stone migration (p = 0.03). Additionally, severe moderate complications for catching calculi in the ureter could be avoided. Furthermore, our series had no complication requiring open and/or laparoscopic conversion (i.e. ureter avulsion; Satava grade 3). We know the limitations in this series. We did not perform molecular studies, dose titration of thiocochicoside, and no comparison with published series with endoscopic devices that were used to prevent stone migration. Additionally, we do not have enough equipment for measuring the pressure in the ureter during the operation. We focused on the evaluation of the effects of thiocolchicoside during ureteroscopy. The main goal of this clinical trial was to investigate whether thiocolchicoside could relax the smooth muscles of the ureter. Decreased occurrences of stone migration and usage of jj stents were recorded. Despite the limitations listed above, this series is the first in the published literature where thiocolchicoside was induced in moderate doses during ureteroscopy. Significant parameters were highlighted, and no adverse effects due to thiocolchicoside were noted. In conclusion, thiocolchicoside seemed safe and effective in irrigating solution during ureteroscopy. It can reduce stone migration during the endoscopic treatment of ureteral calculi. Additional doses of thiocolchicoside may decrease operation time and usage of jj stents. Therefore, ureteroscopy for ureteral calculus can be less invasive. However, molecular studies and dose titration should be
5
done. Also more standardized studies on this issue are needed. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. http://www.uroweb.org/gls/pdf/22%20Urolithiasis_LR.pdf. last accessed at 02.23.2015. 2. Masarani M, Dinneen M. Ureteric colic: new trends in diagnosis and treatment. Postgrad Med J. 2007;83:469–72. 3. Wolf JS Jr. Treatment selection and outcomes: ureteral calculi. Urol Clin North Am. 2007;34:421–30. 4. Pagnani CJ, El Akkad M, Bagley DH. Prevention of stone migration with the Accordion during endoscopic ureteral lithotripsy. J Endourol. 2012;26:484–8. 5. Ding H, Wang Z, Du W, Zhang H. NTrap in prevention of stone migration during ureteroscopic lithotripsy for proximal ureteral stones: a meta-analysis. J Endourol. 2012;26:130–4. 6. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240: 205–13. 7. Akin Y, Yucel S, Danisman A, Erdogru T, Baykara M. The impact of metabolic risk management on recurrence of urinary stones. Kuwait Med J. 2012;44:215–18. 8. Vejdani K, Eisner BH, Pengune W, Stoller ML. Effect of laser insult on devices used to prevent stone retropulsion during ureteroscopic lithotripsy. J Endourol. 2009;23:249–51. 9. Feng C, Ding Q, Jiang H, Gao P, Wen H, Gu B, et al. Use of NTrap during ureteroscopic Holmium:YAG laser lithotripsy of upper ureteral calculi. Minim Invasive Ther Allied Technol. 2012;21:78–82. 10. Wu JA, Ngo TC, Hagedorn JC, Macleod LC, Chung BI, Shinghal R. The accordion antiretropulsive device improves stone-free rates during ureteroscopic laser lithotripsy. J Endourol. 2013;27:438–41. 11. Elashry OM, Tawfik AM. Preventing stone retropulsion during intracorporeal lithotripsy. Nat Rev Urol. 2012;9:691–8. 12. Gerges FJ, Kanazi GE, Jabbour-Khoury SI. Anesthesia for laparoscopy: a review. J Clin Anesth. 2006;18:67–78. 13. Lahoti G. To evaluate efficacy and safety of fixed dose combination of aceclofenac + paracetamol + thiocolchicoside (acenac-MR) in the treatment of acute low back pain. J Indian Med Assoc. 2012;110:56–8. 14. Kertmen H, Gürer B, Yilmaz ER, Arikok AT, Demirci A, Gökyaprak SM, et al. The effect of thiocolchicoside on cerebral vasospasm following experimental subarachnoid hemorrhage in the rabbit. Acta Neurochir. (Wien). 2012;154:1431–6. 15. Oppenheim RW, Calderó J, Cuitat D, Esquerda J, Ayala V, Prevette D, et al. Rescue of developing spinal motoneurons from programmed cell death by the GABA(A) agonist muscimol acts by blockade of neuromuscular activity and increased intramuscular nerve branching. Mol Cell Neurosci. 2003;22:331–43. 16. Ferrari MP, Gatti G, Fattore C, Fedele G, Novellini R. Comparative bioavailability and tolerability study of two intramuscular formulations of thiocolchicoside in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2001;26:257–62.
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17. Harmon WJ, Sershon PD, Blute ML, Patterson DE, Segura JW. Ureteroscopy: current practice and long-term complications. J Urol. 1997;157:28–32. 18. Deliveliotis C, Chrisofos M, Gougousis E, Papatsoris A, Dellis A, Varkarakis IM. Is there a role for alpha1-blockers in treating double-J stent-related symptoms? Urology. 2006; 67:35–9.
19. Damiano R, Oliva A, Esposito C, De Sio M, Autorino R, D’Armiento M. Early and late complications of double pigtail ureteral stent. Urol Int. 2002;69:136–40. 20. Tepeler A, Resorlu B, Sahin T, Sarikaya S, Bayindir M, Oguz U, et al. Categorization of intraoperative ureteroscopy complications using modified Satava classification system. World J Urol. 2014;32:131–6.
ISSN: 1364-5706 (Print) 1365-2931 (Online) Journal homepage: http://www.tandfonline.com/loi/imit20
Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study Yigit Akin, Hakan Gulmez, Mutlu Ates, Erhan Ates & Mehmet Baykara To cite this article: Yigit Akin, Hakan Gulmez, Mutlu Ates, Erhan Ates & Mehmet Baykara (2015): Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study, Minimally Invasive Therapy & Allied Technologies To link to this article: http://dx.doi.org/10.3109/13645706.2015.1067627
Published online: 14 Jul 2015.
Submit your article to this journal
Article views: 2
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=imit20 Download by: [University of Tasmania]
Date: 27 September 2015, At: 03:55
Minimally Invasive Therapy. 2015; Early Online, 1–6
ORIGINAL ARTICLE
Impact of using thiocolchicoside during endoscopic ureteral calculi removal: A preliminary study
YIGIT AKIN1, HAKAN GULMEZ2, MUTLU ATES3, ERHAN ATES4, MEHMET BAYKARA5
Downloaded by [University of Tasmania] at 03:55 27 September 2015
1
Department of Urology, Harran University School of Medicine, Sanliurfa, Turkey, 2Department of Family Medicine, Duzce University School of Medicine, Duzce, Turkey, 3Department of Urology, Memorial Antalya Hospital, Antalya, Turkey, 4Department of Urology, Kahramanmaras State Hospital, Kahramanmaras, Turkey, and 5Department of Urology, Akdeniz University School of Medicine, Antalya, Turkey
Abstract Objective: To evaluate the effects of thiocolchicoside during endoscopic treatment of ureteral calculus. Material and methods: Between May 2014 and December 2014, 498 consecutive patients were enrolled. Exclusion criteria were operations under general anaesthesia, chancing laser lithotripter settings, and urinary tract infection. All patients were divided into three groups: Group 1 consisted of patients who were not administered thiocolchicoside, group 2 consisted of patients who were administered 5 mg thiocolchicoside, and group 3 consisted of patients who were administered 10 mg thiocolchicoside. Demographic, perioperative, and postoperative data were recorded. Complications were noted according to Clavien-Dindo classifications. A p value of p £ 0.05 was considered statistically significant. Results: A total of 427 patients (319 male and 108 female) with full data were investigated. Mean age was 43.3 ± 13.3 years. There were 157 patients in group 1, 141 patients in group 2, and 129 patients in group 3. Stone migration and operation time were significantly lower in groups 2 and 3 than in group 1 (respectively; p < 0.001, p = 0.03). However, usage of jj stents was significantly lower in group 3 than in the other groups (p < 0.001). Conclusion: Stone migration can be decreased by using locally administered thiocolchicoside in irrigation solution during endoscopic treatment of ureteral calculus. Additional doses may decrease usage of jj stents and operation time.
Key words: Endoscopic lithotripsy, holmium laser, skeletal muscle relaxants, ureteral calculi
Introduction Urinary stone disease is still a problem worldwide (1). The rate of urinary stones was recently concluded to be almost equal in both genders (1). Although diagnostic tools and treatment facilities have been developing, urinary stone disease requires manpower (2). Treatment options depend on stone type, place, and presence of metabolic disorders. The ureter is usually affected in the course of urinary stone disease. When the diameter of the ureter calculus is £5 mm, it is usually reduced spontaneously (1). If the ureter stone cannot be reduced spontaneously, endoscopic treatment options come into question (3). Ureteroscopy by semi-rigid ureterorenoscope and laser
lithotripsy is accepted as gold standard the for endoscopic treatment for ureteral calculus (1). However, ureteroscopy may not be easy to perform. Besides, the ureter calculus may migrate to the kidney due to irrigation and/or during fragmentation (4). Moreover, the ureter orifice may be tight and ureteral access may not be provided. Additional devices such as guide-wires and ureteral balloons are used for dilating the ureteral orifice. Additionally, if the patient is under general anaesthesia, a peripheral muscle relaxant may help us to access the ureter. At the end of these measures, the ureter may be damaged. Thus, clinicians may use jj stents. The ureteral calculus is now placed in the kidney and a simple endoscopic treatment procedure of ureteral calculi may become complex. At that time, the treatment
Correspondence: Y. Akin, Department of Urology, Harran University School of Medicine, 63100, Sanliurfa, Turkey, Fax: +90-414-318 3005, E-mail: [email protected] ISSN 1364-5706 print/ISSN 1365-2931 online 2015 Informa Healthcare DOI: 10.3109/13645706.2015.1067627
Downloaded by [University of Tasmania] at 03:55 27 September 2015
2
Y. Akin et al.
procedure of urolithiasis may become a vicious circle for patients. To date, some devices have been presented for preventing ureteral calculi migration during ureteroscopy (5). The aim of ureteroscopy is to remove the stone and not to damage the ureter during the procedure. To date, no study has been published on locally administered drugs for preventing stone migration during uretroscopy. We investigated the effects of the central skeletal muscle relaxant drug thiocolchicoside during endoscopic treatment of ureteral calculus. Our hypothesis was that thiocolchicoside may relax the smooth muscles of the ureter, and thus lower the stone migration rate; usage of jj stents and ureteral dilatation balloon might be provided. This is the first clinical trial study in which thiocolchicoside was administered in irrigating solution of ureteroscopy during treatment of ureter calculus.
Material and methods We performed a retrospective analysis of prospectively recorded data. Patient data were recorded on a Microsoft Excel spreadsheet. The ethical committee approved the study and all patients signed consent forms. Exclusion criteria were operations under general anaesthesia, chancing laser lithotripter settings, and urinary tract infection. Indications for ureteroscopy and laser lithotripsy were accepted as defined in the guidelines of the European Association of Urology on urolithiasis (1). Between May 2014 and December 2014, 498 consecutive patients underwent endoscopic treatment or ureteral calculus.
Data collection Demographic data were collected including age (years), body mass index (BMI) kg/m2, American Society of Anaesthetists (ASA) score, comorbidities, urinary tract infection, diameter and location of ureter calculi, previous urinary stone disease, serum haemoglobin and creatinine, upper urinary tract dilatation in radiology evaluation (ultrasonography and/or non-enhanced computed tomography); perioperative data were collected including usage of thiocolchicoside, ureteral dilatation balloons, stone cone, stone migration, stone-free rate, amount of irrigation solution; postoperative data collected included complications and hospital stay. All complications were evaluated according to the Clavien-Dindo complication classification (6). Thiocolchicoside 5 mg and 10 mg were administered in the first irrigation solution varying among
groups during the operations. All patients were divided into three groups; group 1 consisted of patients who were not administered thiocolchicoside, group 2 consisted of patients who were administered 5 mg thiocolchicoside, and group 3 consisted of patients who were administered 10 mg thiocolchicoside.
Endoscopic ureter calculi treatment All patients received regional anaesthesia. Then, a 9.5f semi-rigid ureteroscope (Karl Storz, Tuttlingen, Germany) was used in the lithotomy position. A Holmium YAG laser (Elmed, Istanbul, Turkey) with a 5.5f laser probe was used for lithotripsy. The settings of the laser generator were 2.5 J with 5Hz in the 15 W. In general, only one irrigation was sufficient for the operation, as 3000cc 0.9% saline. Specifically, a guide-wire was used in male patients for accessing the ureter. A basket catheter was used for collecting fragmented calculus and a stone cone was used for reducing stone migration. In case of upper urinary tract dilatation, ureter damage during stone removal, stone migration, and slight stenosis in the orifice, jj stents were used. At the end of the operation, a 16f foley catheter was indwelled. All stone fragments were sent for analysis to the mine research institute of our community’s government (7). All patients were hospitalized for at least 24 hours after the operation. They were discharged on the first postoperative day after the catheter was removed. The jj stents were removed according to clinical follow-up after stone fragments were reduced or the upper urinary dilatation was decreased. Extra shock wave lithotripsy was performed when the stone could not be reduced. Stone fragments and nephroliths were followed-up by kidney ureter bladder x-ray and/or non-enhanced computed tomography in case of non-opaque calculi.
Statistical analyses We used the standard package in social research (SPSS) V16.0 for statistical analyses. The paired t tests were used for comparing variables. Significant p value was defined as p £ 0.05.
Results A total of 427 patients with full data were enrolled in the study. The mean age was 43.3 ± 13.3 years. There were 319 male and 108 female patients. The mean
3
Impact of thiocolchicoside on ureteral stone removal Table I. Demographic data of groups. Parameters
Group 1 (n = 157)
Group 2 (n = 141)
Group 3 (n = 129)
p value
Gender
35/122 (F/M)
30/111 (F/M)
33/96 (F/M)
0.68
ASA score
1.22 ± 0.41
1.20 ± 0.4
1.29 ± 0.52
0.17
Age (years)
41.9 ± 11.2
42.7 ± 11.9
43.3 ± 13.3
0.06
BMI (kg/m )
26.2 ± 3.9
26.6 ± 3.8
26.1 ± 4.1
0.5
UTI before operation
28
31
27
0.6
Comorbidities
51
40
37
0.6
Stone history
72
63
64
0.7
Previous operation
54
40
37
0.4
0.4
2
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Medical expulsive treatment No
26
17
16
NSAI
92
101
96
a-blocker
39
23
17
Lower
63
61
56
Medium
46
44
38
Upper
48
36
35
Grade 0
29
28
22
Grade 1
43
37
31
Grade 2
43
42
41
Grade 3
42
34
35
8.46 ± 3.06
7.69 ± 2.91
7.86 ± 3.33
Ureter calculi location 0.6
Upper urinary tract dilatation on site of ureter calculi
Stone size
0.7
0.7
Abbreviations: ASA: American Society of Anaesthesiologists, BMI: Body mass index, NSAI: Non-steroidal anti-inflammatory, UTI: Urinary tract infection.
body mass index was 26.3 ± 4.1 kg/m2. There were 157 patients in group 1, 141 patients in group 2, and 129 patients in group 3. There was no urinary tract infection before the operation. Besides, there were no statistical differences among groups, according to the demographic data (Table I). The location and mean size of ureteral calculi, rate of kidney dilatation at the site of the ureteral calculi, and usage of ureteral dilatation balloons were similar in all groups (Table I). Stone migration and operation time were significantly lower in groups 2 and 3 than in group 1 (respectively; p < 0.001, p = 0.03; Table II). However, usage of jj stents was significantly lower in group 3 than in the other groups (p < 0.001). However, hospital stay, postoperative complications, and stone analyses were similar among groups. These data are summarized in Table II. The most common postoperative complication was haematuria, and this was treated by intravenous hydration (Clavie-Dindo Class 1). Five patients in
group 1, two patients in group 2, and four patients in group 3 had postoperative fever due to urinary tract infection. They needed additional antibiotics (Clavien-Dindo Class 2). In total, 11 patients (six patients in group 1, four patients in group 2, and one patient in group 3) needed jj stents under local anaesthesia due to increased lumbar pain after the operation (Clavien-Dindo Class 3). The present series had no Clavien-Dindo class 4 and 5 complications.
Discussion The present study demonstrated a significant decrease in usage of jj stents and stone migration by locally administered moderate doses of thiocolchicoside (5/10 mg) during endoscopic treatment of ureteral calculi. Furthermore, these were associated with a significant decrease in operation time. Additionally, less urinary tract infections occurred after
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Y. Akin et al.
Table II. Perioperative and postoperative data of groups. Parameters
Group 1 (n = 157)
Group 2 (n = 141)
Group 3 (n = 129)
p value
Stone migration
16/141 (Yes/No)
7/134 (Yes/No)
4/125 (Yes/No)
0.03*
Operation time (min.)
43.6 ± 16.2
32.5 ± 14.4
27.6 ± 7.8
< 0.001*
Usage of jj stent
61
30
25
< 0.001*
Hospital stay
1.19 ± 0.52
1.11 ± 0.42
1.08 ± 0.34
0.07
Postoperative complications
13/144 (Yes/No)
6/135 (Yes/No)
4/125 (Yes/No)
0.1
Ca-oxalat
131
121
110
0.8
Struvit
17
15
13
Uric acid
9
5
6
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Stone analyses
*Statistical significant p value.
ureteroscopy in group 3, in which 10 mg thiocolchicoside was used, than in other groups. As a result, usage of thiocolchicoside in irrigating solution (approximate rationale was 5 mg/3000 cc in group 2 and 10 mg/ 3000 cc in group 3) was beneficial during ureteroscopy for the treatment of ureter calculi. Moreover, we excluded patients who underwent ureteroscopy under general anesthesia because we wanted to eliminate any effects of other peripheral muscle relaxant drugs. Even though numerous devices and operation techniques have been described, according to our best knowledge no drug for reducing stone migration during ureteroscopy has been investigated to date (8–10). Stone cone is an endoscopic device that can reduce stone migration during ureteroscopy. Although stone migration can be managed by using this device, it is associated with considerable cost. Nevertheless, there is still a lack of drug-based studies in the published literature (11). This may be due to the fact that most peripheral muscle relaxant drugs are used via the parenteral route and side effects may be life-threating (12). Thicolchicoside is a central muscle relaxant and has been safely used by oral and parenteral route for years (13). Because it is a central muscle relaxant agent, it connects on gamma-aminobutyric (GABA) receptors as agonist (14). However, there are peripheral branches of the central nervous system around the ureter, and all receptors of GABA are located in these branches (15). Recently, Kertmen et al. reported muscle relaxant effects of thiocolchicoside on the vascular plain muscles of brain vessels in a rabbit model (14). They showed that thiocolchicoside affected the smooth muscles of vessels in the brain. We strongly think that the results of the present study can be interpreted along the same
line. Thiocolchicoside directly affects the peripheral branches of neurons and GABA receptors. Thiocolchicoside is a central muscle relaxant drug, and no paper has been published to date describing the rationale for using this drug on the ureter; the same holds true for preclinical in vitro studies on ureter muscle strips and characterization of the sensitive receptors, drug-binding features, pharmacokinetic data, electrophysiological cause-effect studies. It is a well-known truth that GABA receptors are affected by central muscle relaxant agents (13). We used the locally administered forms by adding these in moderate doses in the first irrigating solution of ureteroscopy. In the present study, our hypothesis was that when thiocolchicoside was induced in irrigating solution, it connects to its own GABA receptors of peripheral neurons related to the urothelial mucosa and the ureter. Thus, the smooth muscles of the ureter can relax in a mechanism similar to that published by Kertmen et al. (14). In this set-up, the possible mechanism consists of affecting its GABA receptors and thus chloride enters into neuron cells. This then leads to inhibit voltage-activated Ca2+ in the postsynaptic smooth muscles and in peripheral neuromuscular junctions. Thus, the smooth muscles of the ureter could relax. The present series can be seen as a proof of that mechanism. We did not meet any side effects of thiocolchicoside in the present series. It is known that the bioavailability of thiocolchicoside is as low as 25% (16). This can be overcome by using this in the irrigating solutions. Dose titration may come into question. Taken together, thiocolchicoside was effective in irrigation solution of ureteroscopy. However, more molecular studies are needed to describe the exact mechanism.
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Impact of thiocolchicoside on ureteral stone removal The jj stents are widely used for the management of ureteral obstruction and to prevent complications after ureteroscopy; patient discomfort can come into question (17). High pressure transmitted to the renal pelvis, as well as trigonal irritation by the intravesical part of the stent, constitute some factors of irritation. Additionally, Deliveliotis et al. reported stent-related pain and urinary frequency (18). These symptoms continue until stent removal. On the other hand, Damiano et al. reported complications of jj stents such as bacteriuria, stent migration, and haematuria (19). In the present study we found that moderate doses of thiocolchicoside could reduce usage of jj stents. However, complications and discomfort can be reduced by using less jj stents during ureteroscopy; the exact molecular mechanism should be shown in future detailed studies. Tepeler et al. evaluated intraoperative complications of ureteroscopy by using the Satava classification (20). Stone migration was classified as a type 2 complication. According to our results, using intracorporeal thiocolchicoside significantly prevented stone migration (p = 0.03). Additionally, severe moderate complications for catching calculi in the ureter could be avoided. Furthermore, our series had no complication requiring open and/or laparoscopic conversion (i.e. ureter avulsion; Satava grade 3). We know the limitations in this series. We did not perform molecular studies, dose titration of thiocochicoside, and no comparison with published series with endoscopic devices that were used to prevent stone migration. Additionally, we do not have enough equipment for measuring the pressure in the ureter during the operation. We focused on the evaluation of the effects of thiocolchicoside during ureteroscopy. The main goal of this clinical trial was to investigate whether thiocolchicoside could relax the smooth muscles of the ureter. Decreased occurrences of stone migration and usage of jj stents were recorded. Despite the limitations listed above, this series is the first in the published literature where thiocolchicoside was induced in moderate doses during ureteroscopy. Significant parameters were highlighted, and no adverse effects due to thiocolchicoside were noted. In conclusion, thiocolchicoside seemed safe and effective in irrigating solution during ureteroscopy. It can reduce stone migration during the endoscopic treatment of ureteral calculi. Additional doses of thiocolchicoside may decrease operation time and usage of jj stents. Therefore, ureteroscopy for ureteral calculus can be less invasive. However, molecular studies and dose titration should be
5
done. Also more standardized studies on this issue are needed. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. http://www.uroweb.org/gls/pdf/22%20Urolithiasis_LR.pdf. last accessed at 02.23.2015. 2. Masarani M, Dinneen M. Ureteric colic: new trends in diagnosis and treatment. Postgrad Med J. 2007;83:469–72. 3. Wolf JS Jr. Treatment selection and outcomes: ureteral calculi. Urol Clin North Am. 2007;34:421–30. 4. Pagnani CJ, El Akkad M, Bagley DH. Prevention of stone migration with the Accordion during endoscopic ureteral lithotripsy. J Endourol. 2012;26:484–8. 5. Ding H, Wang Z, Du W, Zhang H. NTrap in prevention of stone migration during ureteroscopic lithotripsy for proximal ureteral stones: a meta-analysis. J Endourol. 2012;26:130–4. 6. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240: 205–13. 7. Akin Y, Yucel S, Danisman A, Erdogru T, Baykara M. The impact of metabolic risk management on recurrence of urinary stones. Kuwait Med J. 2012;44:215–18. 8. Vejdani K, Eisner BH, Pengune W, Stoller ML. Effect of laser insult on devices used to prevent stone retropulsion during ureteroscopic lithotripsy. J Endourol. 2009;23:249–51. 9. Feng C, Ding Q, Jiang H, Gao P, Wen H, Gu B, et al. Use of NTrap during ureteroscopic Holmium:YAG laser lithotripsy of upper ureteral calculi. Minim Invasive Ther Allied Technol. 2012;21:78–82. 10. Wu JA, Ngo TC, Hagedorn JC, Macleod LC, Chung BI, Shinghal R. The accordion antiretropulsive device improves stone-free rates during ureteroscopic laser lithotripsy. J Endourol. 2013;27:438–41. 11. Elashry OM, Tawfik AM. Preventing stone retropulsion during intracorporeal lithotripsy. Nat Rev Urol. 2012;9:691–8. 12. Gerges FJ, Kanazi GE, Jabbour-Khoury SI. Anesthesia for laparoscopy: a review. J Clin Anesth. 2006;18:67–78. 13. Lahoti G. To evaluate efficacy and safety of fixed dose combination of aceclofenac + paracetamol + thiocolchicoside (acenac-MR) in the treatment of acute low back pain. J Indian Med Assoc. 2012;110:56–8. 14. Kertmen H, Gürer B, Yilmaz ER, Arikok AT, Demirci A, Gökyaprak SM, et al. The effect of thiocolchicoside on cerebral vasospasm following experimental subarachnoid hemorrhage in the rabbit. Acta Neurochir. (Wien). 2012;154:1431–6. 15. Oppenheim RW, Calderó J, Cuitat D, Esquerda J, Ayala V, Prevette D, et al. Rescue of developing spinal motoneurons from programmed cell death by the GABA(A) agonist muscimol acts by blockade of neuromuscular activity and increased intramuscular nerve branching. Mol Cell Neurosci. 2003;22:331–43. 16. Ferrari MP, Gatti G, Fattore C, Fedele G, Novellini R. Comparative bioavailability and tolerability study of two intramuscular formulations of thiocolchicoside in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2001;26:257–62.
6
Y. Akin et al.
Downloaded by [University of Tasmania] at 03:55 27 September 2015
17. Harmon WJ, Sershon PD, Blute ML, Patterson DE, Segura JW. Ureteroscopy: current practice and long-term complications. J Urol. 1997;157:28–32. 18. Deliveliotis C, Chrisofos M, Gougousis E, Papatsoris A, Dellis A, Varkarakis IM. Is there a role for alpha1-blockers in treating double-J stent-related symptoms? Urology. 2006; 67:35–9.
19. Damiano R, Oliva A, Esposito C, De Sio M, Autorino R, D’Armiento M. Early and late complications of double pigtail ureteral stent. Urol Int. 2002;69:136–40. 20. Tepeler A, Resorlu B, Sahin T, Sarikaya S, Bayindir M, Oguz U, et al. Categorization of intraoperative ureteroscopy complications using modified Satava classification system. World J Urol. 2014;32:131–6.
