Introduction

OAB is a common condition that can significantly impact quality of life [1, 2]. Although behavioral modification, pelvic floor re-education, and oral medications are first- and second-line treatments, 65–86% of patients stop medical treatments within one year of starting oral therapy due to inadequate efficacy and/or unacceptable tolerability [3]. This has resulted in a large proportion of patients who have failed conservative and medical therapies and who are then eligible for third-line treatment. The most commonly prescribed third-line option is OnabotulinumtoxinA (BTA: Botox® Allergan, Irvine, CA).

Numerous studies [4] have demonstrated the safety and efficacy of BTA injected into the bladder body sparing the trigone as indicated by the FDA label. However, within 6 months of injection, about a third of patients experience dysuria and/or a UTI and 6.5% develop urinary retention requiring catheterization, the rate being even higher for diabetic patients [5]. However, Kuo’s unit in Taiwan reported that trigone-only injections had a lower impact on voiding function, in particular, they reported no acute urinary retention with this technique [6, 7].

At our institution, one provider performs the standard 20 injection trigone-sparing approach while another has adopted the simpler single intra-trigonal injection technique. Therefore, we decided to compare the two approaches to determine if in these clinical practices, there was a difference in outcomes.

Methods

Study design

This study was a retrospective single-institution chart review to allow for a comparison of 2 cohorts. Institutional Review Board approval was obtained. The BTA used was OnabotulinumtoxinA (Botox®, Allergan, Irvine CA). The injection techniques compared were (A) a single trigone-only injection (100 u in 10 ml) and (B) 20 trigone-sparing injections in 4 rows of 5 bladder body sites (100 u in 10 ml total, 0.5 ml per injection) as shown in Fig. 1. The BoNee needle made by Coloplast with either a 0- or 12-degree scope was used for both techniques. The single trigone-only injection punctured the urothelium and was then tunneled forward intramurally towards the dome. Methylene blue dye was employed in the injection for ease of visualization and observation of spread in both techniques [8].

Fig. 1
figure 1

Diagram demonstrating injection sites for (a) trigone-only and (b) trigone-sparing onobotulinumtoxinA. Animated elements from this figure are from Servier Medical Art Commons Attribution 3.0 Unported License http://smart-servier.com

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All patients were instructed to void immediately post-procedure prior to discharge and then followed up at two weeks for a PVR assessment. Patients with high PVR levels (greater than 150 ml) were classed as having some degree of impaired bladder contractility as patients with normal voiding function rarely have a PVR of greater than 150 ml [9]. Intermittent catheterization was required if patients were unable to void post-procedure (acute urinary retention) or if at Week 2, PVR > 300 ml. Patients were scheduled for a subsequent injection after 6 months, but advised to come back earlier if they experienced a recurrence of OAB symptoms. The interval between injections in days was used to determine the durability. Urine cultures were obtained by catheterization only if patients reported symptoms and these were defined as positive on culture if there were more than 105 colonies per high power field. The duration of the injection procedure was documented in minutes as the time from scope insertion to removal. The number of years of independent practice for each surgeon was also documented.

Inclusion and exclusion criteria

All patients who received BTA injections for refractory idiopathic OAB at an outpatient surgery center from January 2016 to December 2018 had their charts reviewed and data extracted to populate the database. Patients were included in the study only if they had failed at least one medical therapy and received at least two BTA injections. Patients were excluded if they had neurogenic bladder, intermittent catheterization was pre-planned, had hybrid trigone and bladder body injections, or if they only received one injection in the study time frame, as durability could not be determined.

Statistical analysis

Statistical analyses were performed on outcomes of each injection procedure with SPSS v. 22.0 (Armonk, NY: IBM Corp). Independent sample t-tests were run to compare the trigone-only and trigone-sparing approaches. A p value of less than 0.05 was considered statistically significant.

Results

The study composed of 45 patients whose demographics were equivalent as shown in Table 1. The clinical outcomes by injection site are displayed in Table 2. No patients had reported symptoms of vesico-ureteral reflux (VUR), such as flank pain, recurrent cystitis, or pyelonephritis. The patients in whom a trigone-only injection (10 ml) was administered, the blue dye was noted to have spread cephalad beyond the trigone but the degree of spread was not measured. The durability based on inter-injection interval was the same for both groups, but the single trigone-only injection resulted in a lower PVR, a lower incidence of significant PVR (> 150 ml) and catheterization rates. The time for the procedure was on average 25% shorter in the single injection trigone-only group even though that provider had been in independent practice for a much shorter time.

Table 1 Demographic data
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Table 2 Clinical outcomes by mode of injection
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Discussion

Our small pilot observational study suggests that a single BTA injection into the trigone is as safe and durable as the recommended 20 trigone-sparing injections, both groups having received 100 u BTA in a total of 10 ml. The durability with both techniques is comparable to that noted in the literature [10, 11]. Of greater importance is that a single trigone-only injection is quicker to perform even in less experienced hands, has no increased risk of VUR, and has a lower impact on voiding function, suggesting that it might be a superior approach. To the best of our knowledge, this is the first real-world report comparing these two injection techniques.

Obviously, a single injection is easier and should be quicker to perform than 20 injections but the time difference in our study, while statistically significant could not be said to be clinically significant. However, we would argue that the speed of the procedure is dependent on experience, so for a given level of experience, a single injection would take less operating time than the standard 20 injections and therefore would have utility.

The most impactful side effect of BTA bladder injections is retention of urine requiring catheterization and this rate was lower in the single trigone injection group. Also, in this group, PVR was lower as was the rate of high PVR (> 150 ml). Other authors have chosen PVR cut-offs of > 200 ml with symptoms or > 350 ml without symptoms [12, 13] but we believe these are artificial cut-offs and likely include patients with some degree of impairment of bladder contractility as normal subjects without voiding dysfunction, even with utero-vaginal prolapse, rarely have a PVR > 150 ml [9]. Post-procedural hematuria is not common being 3–4% in the Botox Phase registration trials [5], however, in patients with a bleeding diathesis or those on anticoagulant therapy, this might be more common. While not documented in the present study, it is likely that 20 injections could pose a greater risk of hematuria than just one injection.

Intravesical BTA injections (200u) sparing the trigone were originally approved in the United States by the FDA in 2011 for the treatment of neurogenic bladder [5]. Many of those patients not only had detrusor overactivity, but also detrusor sphincter dyssynergia. Therefore, the therapeutic goal was to paralyze the bladder thus reducing incontinence. Patients had to resort to clean intermittent catheterization for bladder emptying, an appropriate strategy for this patient group. Subsequently BTA for refractory idiopathic OAB administered across 20 injection sites into the detrusor muscle was approved in 2013. The dose was lowered to 100 u to achieve a reduction in the urinary retention rate [12, 13] but the technique mandating trigonal sparing was not changed, presumably to avoid the risk of vesico-ureteric reflux (VUR). Some studies have investigated the effect of including the trigone and reported that there was no VUR [6, 7, 14,15,16,17,18]. Others found that including the trigone in combination with bladder-wide injections resulted in superior efficacy [17, 18]. A meta-analysis of all pertinent studies addressing injection approach revealed no differences between bladder body and bladder body plus trigone intravesical administration in terms of urinary retention, UTI or high PVR [19].

We hypothesize that the site of chemo-denervation with BTA should be the trigone and only the trigone. It is known from animal research that the bladder trigone and base are richly supplied by afferent fibers and that many of these are small unmyelinated C-fibers that may be upregulated in OAB [20]. These C-fibers may be transducing the sensation of urgency whereas A-delta fibers (myelinated) found in the rest of the bladder probably convey the sensation of bladder fullness by acting as stretch receptors. Also, in the rest of the bladder, the detrusor muscle is innervated by cholinergic parasympathetic fibers that are involved in detrusor contraction during normal voiding [21]. Therefore, the goal of treating OAB should be to target chemo-denervation to only the trigonal nerves and thereby inactivating the up-regulated C-fibers that result in OAB symptoms while leaving intact the A-delta and parasympathetic fibers in the rest of the bladder to maintain normal sensation and contractile function. Such a concept of differential targeting of neural supply of the trigone from the rest of the bladder is supported by recent data from selective bladder denervation using radiofrequency ablation that is restricted solely to the trigone. This denervation procedure in a pilot study appears to ameliorate the symptoms of refractory OAB for over a year without causing UTIs or retention of urine [22].

It has been previously demonstrated that one or two BTA injections can be adequate for effect as it is known that the toxin spreads from the site of injection [23, 24]. This could explain why a single injection can be effective, but also that even a trigone-only injection is not without some predisposition to voiding dysfunction, albeit lower, possibly because of spread from the trigone to the body of the bladder as seen in the current study. Unlike BTA injections, the ablation due to radiofrequency is completely confined to the trigone [25] and does not spread, which may explain why it does not cause any impaired voiding [22].

In randomized controlled studies examining trigone-only against trigone-sparing injections, Kuo found that no patient in the trigone-only group had acute urinary retention [6, 7]. It is possible that in our study, in the trigone-only group, we did observe some need for catheterization because the injection contents were directed up towards the bladder dome and thus compounding the effect of toxin spread. The retention rate could potentially be lowered further by not directing the injection material towards the dome and by reducing the volume of injection.

If future studies also prove that a trigone-only approach with a single injection is superior to the current standard multiple injection technique, then, in women, injecting the trigone through the vagina would be a less invasive procedure. Feasibility of this technique has been demonstrated in cadaver studies [26]. This trans-vaginal approach would not require cystoscopy, would be less invasive, likely more comfortable, and may result in an even lower UTI rate if bladder instrumentation is avoided. This hypothesis needs clinical testing.

The limitations of this pilot study include the fact that it was a retrospective review of charts from only one center, the sample population was small, and the follow-up time was limited. In addition, we did not utilize bladder diaries and validated questionnaires at follow-up visits to assess clinical efficacy. The sample sizes were not comparable between groups as there was no randomization and the volume of patients seen by each provider was different. In addition, PVR data were only collected after treatment so we could not control for patients who may have had pre-treatment asymptomatic undiagnosed impaired voiding. Patients were instructed to return every 6 months or earlier if symptomatic, probably making this parameter less sensitive to detect true differences in durability. Notwithstanding the above, these observational data are encouraging enough to warrant a larger-scale study to determine if this information can be reproduced. Future prospective studies should use validated instruments before and after treatment to assess the efficacy, tolerability, quality of life measure changes, patient comfort, and a cost–benefit analysis comparing the two techniques. Should additional studies confirm the utility of a single trigonal injection, then it would be reasonable to adopt this technique as the standard of care.

Conclusion

The results from this pilot observational study suggest that the simpler trigone-only approach may provide equivalent durability, better tolerability, and reduced operation time. This conclusion will remain speculative until large randomized controlled trials and case series with longer follow-up are able to confirm these data.