Bilateral Simultaneous Ureteroscopic (BS-URS) Approach in the Management of Bilateral Urolithiasis Is a Safe and Effective Strategy in the Contemporary Era—Evidence from a Systematic Review

Purpose of Review Ureteroscopic treatment of urolithiasis has become safer and more effective in the modern era. With a rise in the incidence of bilateral urolithiasis, management dilemma of staged single-side ureteroscopy versus bilateral simultaneous ureteroscopy (BS-URS) is often debatable. This review evaluates the current evidence base for bilateral simultaneous ureteroscopic approach in the modern era. Recent Findings A systematic review was conducted from 1990 to June 2016 including all English language articles reporting on outcomes of BS-URS for urolithiasis. Data was split into two periods: period 1: 2003–2012 and period 2: 2013–2016, and analysed using SPSS version 21. A total of 11 studies (491 patients) were identified from a literature search of 148 studies with mean age of 45 years and a male: female ratio of 2:1 and a mean operative time of 69 min (SD = ±15). The initial and final stone-free rate (SFR) was 87 and 93%, respectively. Post-operative stents were placed in 89% of patients with a mean hospital stay of 1.6 days (SD = ±0.5). Overall, there was a significant negative association between case volume (procedures per month) and complication rate (p = 0.045). Mean hospital stay was significantly longer in period 1 (1.9 days, SD = ±0.5) than period 2 (1.3 days, SD = ±0.3) and complications were also significantly higher in period 1 (47%) compared to period 2 (12%) (p < 0.001). There were six studies examining holmium laser (HL) lithotripsy and three examining pneumatic lithotripsy (PL). There were significantly more complications after PL than HL; however, their SFR was similar. Summary Our review shows that the complication rates and hospital stay are significantly reduced in the contemporary data suggesting an improving trend in outcomes following BS-URS. Simultaneous bilateral ureteroscopic treatment of urolithiasis is safe and effective in the modern era. Safety is increased in centers with increased number of procedures performed and with laser lithotripsy.


Introduction
The evolution of sophisticated miniature ureteroscopes and holmium laser technology has significantly reduced morbidity associated with ureteroscopy (URS). Evidence from contemporary literature suggests complications between 2.4 and 8.6% with URS [1,2]. Ureteroscopy is increasing becoming the approach of choice in complex endourological management [2-4, 5•]. Despite this, the management of bilateral urolithiasis is a subject of much contention and debate amongst endourologists worldwide. Staged single-side URS is often employed in preference to a bilateral simultaneous ureteroscopic (BS-URS) approach. The concerns over BS-URS are due to higher morbidity in comparison with a staged approach. However the potential benefits of BS-URS include single anesthetic session and potentially reduced cost associated with treatment. In an era of austerity these are important considerations while making surgical decisions [6][7][8]. A recent systematic review of seven studies evaluating BS-URS did report an overall stone-free rate (SFR) of 90% suggesting it was a feasible strategy. However, they did report an overall complication rate of nearly 50%, although majority of them were Clavien score ≤ II [9]. In this updated review, we aim to evaluate the following: (1) Feasibility, effectiveness and safety of BS-URS approach (2) Outcomes of bilateral simultaneous ureteroscopic BS-URS approach in a contemporary era (3) Factors that predict complications of BS-URS approach

Methods and Materials
Evidence Acquisition: Criteria for Considering Studies for This Review Inclusion criteria: (1) All articles written in the English language (2) Studies reporting on outcomes following BS-URS for urolithiasis (3) Patients of any age Exclusion criteria: (1) Studies reporting on outcomes of BS-URS for nonurolithiasis indication such as malignancy (2) Studies with <10 patients

Search Strategy and Study Selection
The systematic review was performed according to the Cochrane Review and the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The search strategy was conducted to find relevant studies from Ovid Medline without revisions (1996-July 2016), Cochrane L i b r a r y ( 2 0 1 6 ) , C I N A H L ( 1 9 9 0 -J u l y 2 0 1 6 ) , Clinicaltrials.gov, Google Scholar and individual urologic journals.
The search was limited to English language articles between 1996 and July 2016. Authors of the included studies were contacted in the case of data not being available or clear. Level of evidence was assessed using the recommendations set out by the Centre for Evidence-Based Medicine [10].

Data Extraction and Analysis
The following variables were extracted from each study: year of publication, study period, number of patients/ renal units included, operative time, initial and final SFR, lithotripsy fragmentation device, post-operative stent use, stone size (mm), cumulative stone diameter (CSD) (mm) and complications. Complications were graded using the Clavien Dindo classification [9] in all studies. Case volume was calculated as procedures per month during the study period as reported in the individual studies. For subanalysis, the data was divided into historical and contemporary studies by splitting the collated data into Period 1 (2003 to 2012 inclusive) and Period 2 (2013 to July 2016 inclusive) [22••].
Data was collated using Microsoft Excel (version 12.2.4) and analyzed using SPSS (version 21). Chi square test was used for dichotomous data and independent T test for continuous data.

Outcome Measures
Primary outcomes:

Literature Search and Included Studies
Our literature search produced 148 titles of which 131 articles were excluded due to non-relevance based on the title and abstract (see Fig. 1). Six further papers were excluded upon reading the full manuscript leaving 11 papers, which were included in the study [11][12][13][14][15][16][17][18][19][20][21]. Most studies were retrospective in nature and were no randomization or control groups in these studies (see Table 1). All studies reported on BS-URS and associated variables mentioned in the data extraction section.

Definition of Stone-Free Status
There was variation in how 'stone free' status was defined amongst included studies. Four studies defined it as fragments <4 mm [17][18][19]21]. Drake et al. [20], Huang et al. [16] and Gunlusoy et al. [15] defined stone free ≤2 mm, <1 mm and no stones, respectively. The rest did not specify how stone-free status was defined (see Table 5). Imaging modality and the time duration between intervention and imaging is also demonstrated in Table 5.

Post-Operative Characteristics and Patient Outcomes
(1) Operative time: Overall mean operative time was 68.7 min (SD = ±15.2 min), although two studies did not report operative times [12,13].
(2) Proportion of patient requiring insertion of ureteric stent Reporting on post-operative stent insertion was variable. Ten studies reported on post-operative ureteric stent insertion, and of those only two studies reported whether they were inserted bilaterally or unilaterally [18,20]. The study by Darabi et al. [12] was unclear on their results on stent insertion (see Table 4). The overall stent insertion was 88.8%. Of the two studies that reported on bilateral stent insertion the overall bilateral stent insertion rate was 71.6%.  All studies reported on SFR, with a mean initial and final SFR of 87 and 92% respectively [11][12][13][14][15][16][17][18][19][20][21]. The overall ureteric SFR was 94.0% and the overall renal SFR was 81.0%.
(5) Complication rates (Table 7) All studies reported on complications, with an overall complication rate of 25.6% (n = 118). There were a total of 132 complications graded Clavien I-II and 35 complications graded Clavien ≥ III. One paper did not specify what the post-operative complications were [18]. One patient died as a result of a pulmonary embolus after a prolonged operation (175 min) in the study by Hollenbeck et al. [11].

(1) Comparison of historical versus contemporary studies
There was no overall difference in SFR for initial and final SFR between these two time periods. Analysis of the periods 1 and 2 demonstrated a significantly longer hospital stay in period 1 (1.9 days) than in period 2 (1.3 days) (p = 0.034, 95% CI = 0.09 to 1.60). There were significantly more complications in period 1 (40.5%) than period 2 (11.8%) (p < 0.001). Sub-analysis demonstrated significantly more Clavien I-II complications (p < 0.001) and Clavien ≥ III (p < 0.001) in period 1 than period 2 (see Table 7). There was just one Clavien III complication in period 2, which was early stent removal due to stent symptoms.
(2) Predictors of complications: Case volume: Upon regression analysis there was a significant negative association between complication ND not documented, SD standard deviation  Fig. 2). Stone size: There were no other significant correlations between complication rate and stone size (p = 0.16).

Findings of Our Study
In this updated review, a BS-URS approach achieved an overall SFR and complication rate of 92 and 26%, respectively. The mean hospital stay was just under 2 days. Notably, hospital stay and complications are significantly reduced in the contemporary data (from 2013) when compared with historical cohorts (prior to 2013) [22••] (see Fig. 3). Furthermore, the complication rates reported in this review are nearly half those reported in the systematic review by Rai et al. [22••] This data suggest an improving trend of outcomes following BS-URS. Other factors that have significantly improved outcomes are higher case volume per surgeon and the use of holmium laser fragmentation. This is a clear reflection of evolving expertise, endoscopic laser technology and a wider variety of available technique and technology [23][24][25][26][27][28][29][30].

Meaning and Weakness of the Study
Hollenbeck et al. [11] compared staged URS with BS-URS for bilateral urolithiasis in a retrospective case series. They reported that BS-URS was aassociated with added morbidity; however, the cumulative risk with staged URS procedures (14% per procedure) was similar to BS-URS (29%). However, this data has to be viewed with caution owing to its historical nature. Contemporary data from this review suggests a more encouraging trend with regards to complications from BS-URS. There has been a general reluctance to take up bilateral  contemporary BS-URS cohorts (period 2, complication rate of 12%). BS-URS appears a more effective and safer strategy in comparison with its other counterparts. Superior outcomes in high-volume centers and increasing caseload have been demonstrated procedures such as URS [24] and PCNL [25]. This systematic review is the first study to corroborate this observation in the context of BS-URS. This review also demonstrated that complication rates were significantly lower in studies that employed holmium laser fragmentation. These results corroborates with finding of a previous study for impacted ureteric stones, which also revealed a higher SFR with laser lithotripsy [32].

Areas of Future Research
Our review highlights the lack of high quality evidence on BS-URS in the management of urolithiasis, with all studies of evidence level three. With the arrival of new digital ureteroscopes, these outcomes are likely to improve further [33]. The review raises the issue of standardization of study parameters in order to make appropriate comparisons. For example, the SFR definition varied from study to study, as did the modality of post-operative imaging and time between the intervention and imaging. Due to this lack of standardization, the authors recommend interpreting the data in this study with caution. Further prospective, multi-centred studies with standardized SFR, imaging modality and outcome parameters should be conducted in this field [34].

Conclusions
The complication rate and hospital stay for bilateral simultaneous ureteroscopy for urolithiasis are significantly reduced in contemporary studies compared to previous studies. Higher case volume and holmium laser lithotripsy are associated with fewer complications.

Compliance with Ethical Standards
Conflict of Interest Robert M. Geraghty, Bhavan P. Rai and Patrick Jones each declare no potential conflicts of interest. Bhaskar K. Somani reports honoraria from Coloplast and travel expenses covered/reimbursed by Storz.
Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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