|Year : 2018 | Volume
| Issue : 2 | Page : 175-180
Outcome of anastomotic posterior urethroplasty with various ancillary maneuvers for post-traumatic urethral injury. Does prior urethral manipulation affect the outcome of urethroplasty?
Shahbaz Mehmood1, Omer Abdulaziz Alsulaiman1, Waleed Mohammad Al Taweel2
1 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Urology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
|Date of Submission||10-Nov-2017|
|Date of Acceptance||19-Dec-2017|
|Date of Web Publication||09-Apr-2018|
Dr. Waleed Mohammad Al Taweel
Department of Urology, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211
| Abstract|| |
Purpose: We present our success rate and complications of delayed anastomotic urethroplasty (DAU) in patients with post-traumatic posterior urethral injury.
Materials and Methods: This was a retrospective study of patients aged ≥17 years that underwent DAU for post-traumatic posterior urethral injury during 2010–2014. Stricture length was measured by ascending and descending urethrogram. Success of procedure was considered when the patient was free of stricture-ralated obstruction and needed no further intervention. Primary group includes patients who underwent first time delayed urethroplasty while secondary group included patients who had some sort of urethral manipulation in local hospital. Results were analyzed using unpaired t-test, Chi-square test, binary logistic regression, Kaplan–Meier curves, and log-rank test.
Results: Of the 80 male patients, 73 (91.25%) patients underwent primary DAU while 7 (8.75%) patients had secondary DAU. Median age, stricture length, and follow-up were 27.0 ± 12.7, 1.6 ± 0.9, and 3.2 ± 0.9, respectively. Overall, success rate was 83.75% while success rate in primary group was 89.04% and secondary group was only 28.57% (P = 0.0059). Regarding ancillary maneuvers, urethral mobilization alone was done in 29 (36.25%) patients with success rate (72.41%), corporeal body separation in 36 (45%) patients with success rate (91.66%), inferior wedge pubectomy in 13 (16.25%) with success rate (84.61%), supracrural rerouting in 1 (1.25%) with success rate (100%), and abdominoperineal approach in 1 (1.25%) with success rate of 100% (P = 0.193). Patients who had prior urethral manipulation affect the outcome of definitive anastomotic urethroplasty.
Conclusion: DAU has durable success rate with less morbidity. Ancillary elaborated maneuvers are frequently needed in patients with complex and elongated post-traumatic posterior urethral defect with successful outcome.
Keywords: Inferior wedge pubectomy, posttraumatic, urethral mobilization, urethroplasty
|How to cite this article:|
Mehmood S, Alsulaiman OA, Al Taweel WM. Outcome of anastomotic posterior urethroplasty with various ancillary maneuvers for post-traumatic urethral injury. Does prior urethral manipulation affect the outcome of urethroplasty?. Urol Ann 2018;10:175-80
|How to cite this URL:|
Mehmood S, Alsulaiman OA, Al Taweel WM. Outcome of anastomotic posterior urethroplasty with various ancillary maneuvers for post-traumatic urethral injury. Does prior urethral manipulation affect the outcome of urethroplasty?. Urol Ann [serial online] 2018 [cited 2021 Jan 21];10:175-80. Available from: https://www.urologyannals.com/text.asp?2018/10/2/175/229559
| Introduction|| |
Posterior urethral injuries are most commonly associated with pelvic fracture,, with an incidence of 5%–10%. With an annual rate of 20 pelvic fractures per 100,000 populations, these injuries are not uncommon. Pelvic fracture posterior urethral injury (PFPUI) continues to be a surgical challenge in reconstructive urology. The mechanism of posterior urethral injuries due to pelvic fracture and emergency management of these injuries vary worldwide, especially in developing and developed world.,, Complex posterior urethral injuries with pelvic fracture require a greater understanding of all available technique to reconstructive urologist., Otherwise, it can lead to devastating complication such as urinary incontinence, urethracutaneous fistula, and restenosis.
In the 1970s, Turner-Warwick devised a new technique to bridge the defect of 2.5 cm by a delayed one-stage perineal approach of bulboprostatic urethral anastomosis., It is a procedure of choice for posterior urethral injury and provides a decreased incidence of postoperative morbidity, restenosis, and urinary incontinence for short segment post-traumatic urethral injury. There is wide variety of technique available for posterior urethral injury management. Excision and spatulated end-to-end anastomosis is an ideal procedure for single short traumatic stricture of bulbar urethra and posterior urethral defect with varying degree of success in some series.,
In 1991, Webster and Ramon popularized the extended perineal approach using various ancillary maneuvers such as corporeal body separation, inferior pubectomy, and retrocrural urethral rerouting to reduce the gap between bulbar and the prostatic apex. These maneuvers allow better removal of scar tissues and tension-free anastomosis of posterior urethra. Although these ancillary approaches became standard for simple and complex traumatic posterior urethral injury in era of 90s,, few studies from developed countries described the limited role of these maneuvers.,
Another controversial issue is the timing of posterior urethral injury management. The objective of immediate management is to effectively divert urine to expedite the early recovery of patient. Increase rate of erectile dysfunction (ED) and urinary incontinence with immediate management direct reconstructive surgeons to delayed urethroplasty,, but primary urethral alignment appears to reduce the incidence of stricture formation after posterior urethral injury due to pelvic fracture.,,
In this study, we report the outcomes of a series of patients who underwent delayed perineal anastomotic urethroplasty by various ancillary maneuvers and compare surgical success rate with published series.
| Materials and Methods|| |
After the Institutional Review Board approval, retrospective chart reviews were perforformed in all adult patients with PFPUI who underwent delayed anastomotic urethroplasty (DAU) in our tertiary care referral center by a single surgeon. In all patients, history, physical examination, retrograde, and voiding cystourethrography was performed. Intravenous antibiotics were administered perioperatively and then tailored according to urine sensitivity. Patient's data were reviewed by age, etiology of stricture, prior treatment, and ancillary treatment while doing anastomotic urethroplasty. Preoperative stricture length on ascending and descending urethrogram was noted. Pre- and postoperative sexual functional statuses of patients were assessed and documented. Peri- and postoperative complications mentioned in charts were noted.
All patients underwent transperineal excision and anastomotic urethroplasty after taking informed consent. The patients were placed exaggerated lithotomy position and an inverted Y-shaped incision was made in perineum. Incision deepened and bulbar urethra was mobilized from proximal end and transected at the distal end of strictured segment. After excising all scared tissues, the distal urethral end was spatulated. A stepwise approach for urethral mobilization was performed with mobilization of bulbar urethra, separation of cavernosal bodies, and inferior pubectomy was performed in those cases who had a urethral defect of >3 cm in length to achieve tension-free mucosa to mucosa reanastomosis with 5/0 polyglycolic acid sutures over a 16 French silicon catheter. Abdominoperineal approach and supracrural rerouting were reserved for recurrent complex cases of posterior urethral stricture. Procedure was completed by closing the wound with or without drain placement. Suprapubic catheter was retained. Patients were usually discharged at postoperative day 5–7. Pericatheter urethrogram was performed at day 21 to make sure that there was no leakage at anastomotic site. We usually do an uroflowmetry by infusing 200 ml of water through urethral catheter in outpatient clinic and then take out folly catheter. Suprapubic catheter was taken out next day if patient passed urine satisfactorily.
Patients were followed up at regular interval at 3, 6, and 12 months with a history of urinary symptoms, uroflowmetry, and retrograde urethrogram. The surgical success was defined as asymptomatic voiding with no obstructive symptoms, good flow rate on uroflowmetry, and absence of narrowing on urethrogram.
Statistical analyses were performed using SPSS 20.0 software (SPSS, Chicago, IL, USA). Descriptive statistics were analyzed as mean ± standard deviation, postoperative complication like ED; stress incontinence and urethroplasty failure were analyzed by Chi-squared test. Quantitative variable like age was measured with independent samples t-test. Kaplan–Meier curve was used for success rate between patients with primary delayed urethroplasty and patients with prior manipulation and compared with log-rank test. Statistical significance was considered as P ≤ 0.05.
| Results|| |
Eighty male patients were included in the study. Median age at the surgery was 30.56 ± 5.06 years and median follow-up was 3.2 ± 0.9 years. Median length of urethral stricture was 2.7 ± 0.6 cm. Seventy-three (91.25%) patients underwent primary DAU and 7 (8.75%) patients had a history of either primary realignment (n = 3), visual internal urethrotomy (VIU) (n = 2), and urethroplasty (n = 2) done in other center before referral to our institution as shown in [Table 1].
Regarding etiology, 64 (80%) patients had motor vehicle accident, 8 (10%) with a history of fall from height, 6 (7.5%) straddle injury, and 2 (2.5%) with iatrogenic trauma as shown in [Figure 1].
Overall success rate was 83.75% with a Qmax of >18.0 ± 3.2 ml/s at median follow-up of 3.2 ± 0.9 years. Primary group had a success rate of 89.04% while patients in secondary group had a success rate of 28.57% only as shown in [Table 2] and [Graph 1]. Most of the patients with failed urethroplasty referred to our tertiary care center for further management. Thirteen (16.25%) patients underwent redo surgery in which 4 (30.76) patients had redo anastomotic urethroplasty and 9 (69.23%) patients with direct visual internal urethrotomy (DVIU) as mentioned in [Table 3].
Fifty-one (63.75%) patients required ancillary maneuvers to fill the gap to do tension-free anastomosis. These elaborated maneuvers for perineal anastomotic urethroplasty were solely based on complexity and length of strictures as urethral mobilization alone was not sufficient in these patients. The data of these patients are shown in [Table 4] and [Graph 2].
Regarding early and late complications, almost all complications were managed conservatively except recurrent stricture which developed in 13 (16.25%) patients. These patients were successfully managed with redo urethroplasty in four and VIU in nine patients. These complications are mentioned in [Table 5].
| Discussion|| |
Posterior urethral disruption is one of the most challenging dilemmas for reconstructive urologist following pelvic fracture. Surgery for posterior urethral stricture has its own inherent problems because of its difficult access; limited urethral length, surrounding fibrosis, and small diameter of urethra render it susceptible to ischemic insults. Depending on the site, stricture length and possible previous surgery underwent by patients are the factors which determine the type of procedure.,, These include dilatation, VIU, perineal urethral anastomosis, elaborated perineal, and abdominoperineal procedure for urethral reconstruction.,, Similarly, VIU is only feasible in true stricture with intact epithelium and not appropriate in distraction defects where urethral ends are separated by fibrotic tissue. All of our patients had a traumatic urethral stricture underwent perineal anastomotic urethroplasty with elaborated ancillary maneuvers.
Important steps that need to consider avoiding recurrence include maintaining the vascurity of urethra, complete excision of the fibrous tissue, and tension-free anastomosis. Hafez et al. found a success rate of 88% with delayed anastomotic perineal urethroplasty for post-traumatic posterior urethral stricture. He further explained that majority of complications with perineal anastomosis can be avoided by meticulous preoperative evaluation to define anatomy and intraoperative careful manipulation. In our result, we observed a similar result of 89.3% success rate with delayed primary perineal anastomosis. Similarly, Al-Qudah and Santucci  reported 100% success rate for posterior anastomotic urethroplasty and Flynn et al. investigated a recurrence rate of 5% in their 109 patient series who underwent perineal anastomotic urethroplasty. The major cause of recurrent stricture was inadequate excision of fibrotic tissue and mobilization of urethra at the time of surgery. Hence, it is mandatory to completely excise the fibrotic tissue to achieve tensionless, complete, and healthy mucosal anastomosis.
Moreover, it is still debatable whether primary realignment or urethral manipulation impact on overall success rate of salvage anastomotic urethroplasty. Our center is referral center from all over the kingdom. Few of our patients referred to our after several attempts of endoscopic or open repair. In our series, success rate in these patients with previous urethral manipulation was only 28.58% in the first attempt as compared to primary delayed urethroplasty in success rate was 91.25% (log-rank P = 0.0059). Mundy experienced that early endoscopic realignment impedes delayed urethroplasty because of extensive inflammatory fibrotic process in up and down of that urethral part and on either side of injury. Similarly, Wadhwa et al. reported the record of 23 patients in whom perineal anastomotic urethroplasty was unsuccessful for traumatic urethral stricture. Hence, final success rate after salvage urethroplasty was only 14% and satisfactory results were gained in only 28.5% of cases. Hence, previous railroading or urethroplasty decreases the success of subsequent urethroplasty., It can be concluded from above-mentioned studies that immediate manipulation should be avoided in suboptimal conditions and these posterior urethral distraction cases after pelvic trauma should be referred to specialized center with such expertise.
The objective for progressive elaborated perineal maneuvers is to change the geometry of the path required for tension-free anastomosis of dislocated proximal urethral stump to bulbar urethral end. We have used all four progressive perineal maneuvers in our series on the basis of length of distraction defect and complexity of urethral stricture with similar success rate as in published series. Koraitim  reported elaborated maneuvers using clinicoradiological parameters, including a “gapometry”/urethrometry index, urethral gap length, and prostate displacement, to predict which patients need elaborated perineal or transpubic approach and which patients required simple perineal urethroplasty alone. We think that surgeon performing pelvic fracture urethral distraction defect surgeon should be capable of performing all types of elaborated maneuvers. As we have seen in our series, simple looking defect on preoperative radiograph might be totally different on surgical exploration. Similar observation was reported by Andrich et al., who described that 62 men out of 100 there was no association between preoperative measured defect length and scale of surgery required.
Singh et al. reported his progressive elaborated perineal approach in 172 patients, with an overall success rate of 91% while Fu et al. reported an overall success rate of 87.4% in 301 patients. Simple perineal anastomosis was done in 103 (34.2%), perineal anastomosis with separation of the corporal bodies in 89 (29.6%), perineal anastomosis with inferior pubectomy in 95 (31.6%), and perineal anastomosis with supracrural rerouting of the urethra in 14 (4.7%). Of the 301 delayed transperineal bulboprostatic anastomosis procedures, 263 (87.4%) were successful. Simple perineal anastomosis with no ancillary procedures had an 89.3% success rate, perineal anastomosis with separation of the corporeal body an 86.5% success rate, perineal anastomosis with inferior pubectomy an 84.2% success rate, and perineal anastomosis with urethral rerouting an 85.7% success rate. Our series results are very similar with above-mentioned study. We had 72.41% success rate in urethral mobilization alone, 91.66% in corporeal body separation, 84.61% in inferior wedge pubectomy, 100% in supracrural rerouting, and 100% success rate in abdominoperineal approach.
Urinary incontinence is the most common complication after urethroplasty. The incidence of urinary incontinence is <10% and even much lower in some series.,, We have only 1 patient (1.25%) who developed mild stress urinary incontinence which was successfully managed conservatively. Another common complication of posterior urethroplasty is ED. Pelvic fracture is associated with urethral dysfunction and ED. Many studies suggest that it is the primary injury which causes neurovascular damage that leads to ED rather than urethral surgery itself. Clinicians postulate that cavernous nerves and branches internal pudendal artery are located near the apex of prostate and supply the corporeal bodies after entering through the urogenital diaphragm. These neurovascular bundles got damage during pelvic fracture, especially pubic symphysis diastasis.,,,
Limitations in this study need to be considered. The main limitation of our series was its retrospective nature and small number of study patients. Potential bias and reporting errors are the main risks of any retrospective study. We assured that many of these ambiguities were mostly avoided during data collection.
| Conclusion|| |
DAU has durable success rate with less morbidity. Ancillary elaborated maneuvers are frequently needed in patients with complex and elongated post-traumatic posterior urethral defect with successful outcome.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ingram MD, Watson SG, Skippage PL, Patel U. Urethral injuries after pelvic trauma: Evaluation with urethrography. Radiographics 2008;28:1631-43.
Myers JB, McAninch JW. Management of posterior urethral disruption injuries. Nat Clin Pract Urol 2009;6:154-63.
Dixon CM. Diagnosis and acute management of posterior urethral disruptions. McAninch JW, editor. Traumatic and Reconstructive Urology. Philadelphia, Pa: WB Saunders; 1996. p. 347-55.
Kulkarni SB, Barbagli G, Kulkarni JS, Romano G, Lazzeri M. Posterior urethral stricture after pelvic fracture urethral distraction defects in developing and developed countries, and choice of surgical technique. J Urol 2010;183:1049-54.
Mundy AR, Andrich DE. Pelvic fracture-related injuries of the bladder neck and prostate: Their nature, cause and management. BJU Int 2010;105:1302-8.
Barrett K, Braga LH, Farrokhyar F, Davies TO. Primary realignment vs suprapubic cystostomy for the management of pelvic fracture-associated urethral injuries: A systematic review and meta-analysis. Urology 2014;83:924-9.
Kulkarni SB, Joshi PM, Hunter C, Surana S, Shahrour W, Alhajeri F, et al
. Complex posterior urethral injury. Arab J Urol 2015;13:43-52.
Fu Q, Zhang J, Sa YL, Jin SB, Xu YM. Recurrence and complications after trans perineal bulboprostatic anastomosis for posterior urethral strictures resulting from pelvic fracture: A retrospective study from a urethral referral center. BJU Int 2013; 112, E358-63.
Manikandan R, Dorairajan LN, Kumar S. Current concepts in the management of pelvic fracture urethral distraction defects. Indian J Urol 2011;27:385-91.
] [Full text]
Turner-Warwick R. A personal view of the management of traumatic posterior urethral strictures. Urol Clin North Am 1977;4:111-24.
Hafez AT, El-Assmy A, Sarhan O, El-Hefnawy AS, Ghoneim MA. Perineal anastomotic urethroplasty for managing post-traumatic urethral strictures in children: The long-term outcome. BJU Int 2005;95:403-6.
Odoemene CA, Okere P. One-stage anastomotic urethroplasty for traumatic urethral strictures. January 2004-january 2013. Niger J Surg 2015;21:124-9. [Full text]
Eltahawy EA, Virasoro R, Schlossberg SM, McCammon KA, Jordan GH. Long-term followup for excision and primary anastomosis for anterior urethral strictures. J Urol 2007;177:1803-6.
Van den Heever AP, Lazarus J, Naude JH, Wiechers L, Tsheisi M. Retrospective outcome analysis of urethroplasty performed for various etiologies in a single South African centre. Afr J Urol 2012;18:127-30.
Webster GD, Ramon J. Repair of pelvic fracture posterior urethral defects using an elaborated perineal approach: Experience with 74 cases. J Urol 1991;145:744-8.
Mundy AR. Surgical atlas. Anastomotic urethroplasty. BJU Int 2005;96:921.
Andrich DE, Mundy AR. What is the best technique for urethroplasty? Eur Urol 2008;54:1031-41.
Kizer WS, Armenakas NA, Brandes SB, Cavalcanti AG, Santucci RA, Morey AF, et al
. Simplified reconstruction of posterior urethral disruption defects: Limited role of supracrural rerouting. J Urol 2007;177:1378-81.
Lumen N, Hoebeke P, Troyer BD, Ysebaert B, Oosterlinck W. Perineal anastomotic urethroplasty for posttraumatic urethral stricture with or without previous urethral manipulations: A review of 61 cases with long-term followup. J Urol 2009;181:1196-200.
Mouraviev VB, Coburn M, Santucci RA. The treatment of posterior urethral disruption associated with pelvic fractures: Comparative experience of early realignment versus delayed urethroplasty. J Urol 2005;173:873-6.
Aşci R, Sarikaya S, Büyükalpelli R, Saylik A, Yilmaz AF, Yildiz S, et al
. Voiding and sexual dysfunctions after pelvic fracture urethral injuries treated with either initial cystostomy and delayed urethroplasty or immediate primary urethral realignment. Scand J Urol Nephrol 1999;33:228-33.
Chang PC, Hsu YC, Shee JJ, Huang ST, Huang HC, Chen Y, et al
. Early endoscopic primary realignment decreases stricture formation and reduces medical costs in traumatic complete posterior urethral disruption in a 2-year follow-up. Chang Gung Med J 2011;34:179-85.
Hadjizacharia P, Inaba K, Teixeira PG, Kokorowski P, Demetriades D, Best C, et al
. Evaluation of immediate endoscopic realignment as a treatment modality for traumatic urethral injuries. J Trauma 2008;64:1443-9.
Barbagli G. History and evaluation of transpubic urethroplasty: A lesson for young urologists in training. Eur Urol 2007;52:1290-2.
Stein DM, Thum DJ, Barbagli G, Kulkarni S, Sansalone S, Pardeshi A, et al
. A geographic analysis of male urethral stricture aetiology and location. BJU Int 2013;112:830-4.
Koraitim MM. Post-traumatic posterior urethral strictures: Preoperative decision making. Urology 2004;64:228-31.
Koraitim MM. The lessons of 145 posttraumatic posterior urethral strictures treated in 17 years. J Urol 1995;153:63-6.
Chapple C. Anterior urethral surgery: Current concepts and future directions. Eur Urol 2010;58:42-5.
Mundy AR, Andrich DE. Urethral trauma. Part II: Types of injury and their management. BJU Int 2011;108:630-50.
Kurt A, Jack M, Gerald ZH. Surgery of penis and urethra. Wein Aj, Kavousi LR, Partin AW, editors. Campbell-Walsh Urology. 11th ed. Philadelphia: W.B. Saunders; 2016;1:1287-343.
Al-Qudah HS, Santucci RA. Extended complications of urethroplasty. Int Braz J Urol 2005;31:315-23.
Flynn BJ, Delvecchio FC, Webster GD. Perineal repair of pelvic fracture urethral distraction defects: Experience in 120 patients during the last 10 years. J Urol 2003;170:1877-80.
Mundy AR. Pelvic fracture injuries of the posterior urethra. World J Urol 1999;17:90-5.
Wadhwa SN, Chahal R, Hemal AK, Gupta NP, Dogra PN, Seth A, et al
. Management of obliterative posttraumatic posterior urethral strictures after failed initial urethroplasty. J Urol 1998;159:1898-902.
Singh BP, Andankar MG, Swain SK, Das K, Dassi V, Kaswan HK, et al
. Impact of prior urethral manipulation on outcome of anastomotic urethroplasty for post-traumatic urethral stricture. Urology 2010;75:179-82.
Culty T, Boccon-Gibod L. Anastomotic urethroplasty for posttraumatic urethral stricture: Previous urethral manipulation has a negative impact on the final outcome. J Urol 2007;177:1374-7.
Koraitim MM. Predictors of surgical approach to repair pelvic fracture urethral distraction defects. J Urol 2009;182:1435-9.
Andrich DE, O'Malley KJ, Summerton DJ, Greenwell TJ, Mundy AR. The type of urethroplasty for a pelvic fracture urethral distraction defect cannot be predicted preoperatively. J Urol 2003;170:464-7.
Singh SK, Pawar DS, Khandelwal AK, Jagmohan. Transperineal bulboprostatic anastomotic repair of pelvic fracture urethral distraction defect and role of ancillary maneuver: A retrospective study in 172 patients. Urol Ann 2010;2:53-7.
] [Full text]
Fu Q, Zhang J, Sa YL, Jin SB, Xu YM. Transperineal bulboprostatic anastomosis in patients with simple traumatic posterior urethral strictures: A retrospective study from a referral urethral center. Urology 2009;74:1132-6.
Pratap A, Agrawal CS, Tiwari A, Bhattarai BK, Pandit RK, Anchal N, et al
. Complex posterior urethral disruptions: Management by combined abdominal transpubic perineal urethroplasty. J Urol 2006;175:1751-4.
Jordan GH, Schlossberg SM. Surgery of the penis and urethra. In: Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA editors. Campbell-Walsh Urology. 9th
ed. Philadelphia, PA: Saunders; 2007. p. 1054-84.
Feng C, Xu YM, Yu JJ, Fei XF, Chen L. Risk factors for erectile dysfunction in patients with urethral strictures secondary to blunt trauma. J Sex Med 2008;5:2656-61.
Fu Q, Sun X, Tang C, Cui R, Chen L. An assessment of the efficacy and safety of sildenafil administered to patients with erectile dysfunction referred for posterior urethroplasty: A single-center experience. J Sex Med 2012;9:282-7.
Lumen N, Hoebeke P, Willemsen P, De Troyer B, Pieters R, Oosterlinck W, et al
. Etiology of urethral stricture disease in the 21st
century. J Urol 2009;182:983-7.
Sangkum P, Levy J, Yafi FA, Hellstrom WJ. Erectile dysfunction in urethral stricture and pelvic fracture urethral injury patients: Diagnosis, treatment, and outcomes. Andrology 2015;3:443-9.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]