# A Review of the Effect of Injected

Authors: Sumit Dave; Darius J. Bägli
Journal: Advances in Urology
 (2008)

---

## Abstract

The current literature suggests that multiple variables affect vesicoureteric reflux (VUR) resolution rates following dextranomer/hyaluronic acid copolymer (Dx/HA) injection. This article reviews the evidence pertaining to the effect of injected Dx/HA volume on success rates following endoscopic correction. Lack of prospective studies which use injected volume as a continuous variable coupled with a nonstandardized injection technique and endpoint hinders the ability to reach a definite conclusion.


---

## Body

## 1. Introduction

The approval
of dextranomer hyaluronic acid copolymer (Dx/HA) by the FDA in 2001, coupled
with its safety and ease of injection, has led to a rapid increase in its use
for treating vesicoureteral reflux (VUR) [1]. This has been accompanied by a
reevaluation of the treatment philosophy for VUR, promulgated by both a change
in physician preference and driven by parents who are opting for endoscopic
correction over long-term follow up and antibiotic prophylaxis [2, 3]. However,
in the era where basic concepts about VUR and its role in UTI and renal
scarring continue to evolve, the mere availability of a minimally invasive
approach cannot, in of itself, immediately justify the adoption of changed indications
for VUR correction. Moreover, despite the high success rates shown in some
large series, endoscopic VUR correction using Dx/HA has not yet achieved the
success rates following open surgery [4]. It is, therefore, imperative that
factors associated with success following Dx/HA injection are identified in
order to improve surgical outcomes, gain insight into potential mechanisms
which underlie success as well as failure, and enable better patient selection
and preoperative counseling (Table 1).Table 1
Reported variables associated with VUR correction using Dx/HA.
Variables
associated with VUR correction following Dx/HAinjection(1) Mound
morphology(2) Grade of VUR(3) Surgeon
experience/learning curve(4) Injection
technique(5) Volume of
Dx/HA(6) Absence of
ureteric dilatation(7) Location of
ureteral orifice (degree of lateral ectopia)(8) Age of
patient(9) Resident
participation(10) Fewer needle
insertions(11) Absence or
correction of lower urinary tract symptomsThe current paper
reviews the impact of injected Dx/HA volume on primary VUR correction rates.
Studies analyzing this variable are discussed along with the findings of a
recent multivariable analysis conducted at our institution.


## 2. Effect of Injection Technique on the Volume of Dx/HA

The known principles for VUR
correction are derived from dissections dating back to the description of the
physiologic submucosal tunnel by Paquin in 1950s, which defined the mechanistic
basis of open surgical procedures to correct VUR [5]. By extrapolation, the
goal of endoscopic injection is to create an effective valvular surrogate by
providing submucosal support for the entire length of whatever portion of the
refluxing ureter, that is, transvesical. This is achieved by accurate injection
of sufficient amount of the bulking agent in a correct plane. The
hydrodistension implantation technique (HIT) popularized by Kirsch and
subsequently modified to a double HIT procedure has highlighted the importance
of hydrodistension in enabling an intraureteric injection to target support to
the entire intravesical ureter [6]. This technique was based on the initial
description by Chertin et al. for injection therapy in children with high-grade
VUR [7]. As opposed to the classical STING (subtrigonal injection) technique,
which aims at achieving a good mound at the ureteral orifice, the HIT tends to
involve higher volumes of injection as it aims to support the entire ureteric
length. Moreover, obliteration of any further hydrodistension of the ureteral
orifice is the endpoint in this technique rather than a good mound. Clearly,
establishing this endpoint may further lead to higher injection volumes.
Therefore, reported volumes of injection in all studies should be interpreted
with caution, and both technique and volume should be studied as distinct
variables in a multivariable analysis.


## 3. Effect of Injected Dx/HA Volume on Outcome

The mean injected volume of Dx/HA injected
in all series reported to date varies between 0.2 mL to>1 mL [2, 3, 6, 8–16]. The impact
of injected volume on success is variable (Table 2). Kirsch et al. found no
statistical difference in injected volume between successes and failures using
a mean of 0.83 mL in 459 ureters [8]. In a follow up study using a mean volume
of 0.9 mL, the same authors demonstrated a positive impact of increasing
experience as well as injected volume, with improved success rates from 60 to 74%
[6]. The third variable, which then prompted a further improvement in the
success rate to 89%, was the use of the “modified STING” or HIT. The HIT
technique involves placing the needle into the mid to distal ureteral tunnel
itself at the 6-o’ clock position and watching the entire tunnel coapt as the
injection progresses. In contrast, the traditional STING technique, judged   by both the mechanism and endpoint of
injection (a mound at the ureteral orifice alone, not involving the intravesical
ureter, and in
effect creating a surrogate nipple valve rather than flap valve mechanism at
the ureteral orifice to prevent VUR) would presumably require a relatively
lesser injected volume. Though not
highlighted in the paper, the injected volumes were indeed higher in this
subset of patients (1–1.5 mL), compared
to the STING group.Table 2
Studies
investigating the effect of injected Dx/HA volume on VUR correction.
SeriesRefluxing units; meanMeanVolume injected (mL)Method of statisticalSuccess byEffect of volume ofDx/HA volume (mL)gradesuccess/failuresanalysisgrade
(%)injected Dx/HAKirsch 20032922.6S:0.9±0.3UnivariateI 90; II 82;NS0.83±0.03F:0.9±0.2III 73; IV 65Kirsch 2004119S: 1.0I 100; II 90;Highermodified>0.92.8F: 1.5UnivariateIII 91; IV
89volumeSTINGsignificantLavelle80NAS: 0.8UnivariateI 82; II 84;NS2005NAF: 0.9III 77; IV 73Routh225 pts2.4S: 0.8 (0.4–2.0)UnivariateI 63; II 72; III 57;NS20060.8 (0.3–2.0)F: 0.8 (0.3–1.8)IV 14 (By patients)2.6NAStudied
as categoricalI 100; II 83;Lower (<0.5)Yucel259variable with cutoffIII 73;volume20070.54±0.2</>0.5 mL usingIV
53,significantmultivariable
analysisV 292.3NAStudied
as categoricalI 83;NSRouth453variable with cut offII 82;20070.93 (0.2–3.5)</>1 mL usingIII 66;multivariable
analysisIV 533I 100,HigherDave 2007196S:0.9±0.2Studied
as continuousII 75;volume(Accepted J0.8±0.03F:0.6±0.2variable usingIII 57;significant
onUrol)multivariable analysisIV
37;multivariableV 46analysisIn contrast, in two subsequent
studies where mean injected volumes of Dx/HA were≥0.8 mL, no correlation with VUR correction was
noted [9, 10]. Lavelle et al. reported that the  average injected volume was
0.84 mL in those with successful VUR correction when compared with 0.94 mL in
failures (p=NS) [9]. Mound morphology was the only statistically significant
predictor of success; 87% of ureters that showed a “volcano” configuration
were corrected as opposed to only 53% in those with an “alternate” morphology.
Although Routh et al. did not demonstrate an effect of injected volume in their
study, the authors acknowledged that their injection volume had increased over
time based on the positive experience of other authors [10].Yucel et al. performed a
multivariable analysis of their experience with Dx/HA injection and showed that
an injected volume of<0.5 mL was significantly associated with success as
compared to a volume >0.5 mL [11]. The overall reflux correction was 70% by
patients and 78% by ureters (mean VUR grade 2.6) as compared to 89% and 92%,
respectively (mean VUR grade 2.6), in the study by Kirsch et al. [6]. Similar
to the findings of Lavelle et al., this study showed that mound morphology was
the most important indicator of VUR correction. The authors speculated that a
higher volume of Dx/HA implied a technically more difficult injection resulting
in a poorer outcome. No evidence was provided to support this conjecture.
Moreover, it is unlikely that all injections in the HIT series by Kirsch et al.
were uniformly more difficult to alone account for greater injected volumes. As
stated above, a priori
performance of a double HIT injection is likely to require more injected
material. Alternatively, the findings of Yucel et al. may reflect that the
analysis was based on a cutoff close to their mean injected volume, rather than
treating the injected volume as a continuous variable.Another multivariable analysis published in
2007 attempted to look at the effect of volume using a 1 mL cutoff. Routh et al.
treated 301 patients (453 ureters) with VUR using an average 0.93 mL Dx/HA with
a 75.5% success rate by ureters [12]. The authors noted that preoperative VUR
grade and the operating surgeon were significant predictors of outcome. The
technique of injection (HIT versus STING) was significant on a univariate
analysis but only showed a trend toward significance for HIT on a multivariable
analysis (P=.056). However, with respect to volume, no difference in
success rates was noted when injected Dx/HA volume was analyzed as a cutoff of
<1 mL or >1 mL. It is possible that arbitrarily choosing a 1 mL cutoff
volume may have missed an actual significant cutoff volume, thereby, failing to
detect any volume effect. Moreover, as rightly pointed out by the authors,
there is also a possibility that the positive effect of higher volume is
nullified by the fact that higher volumes are more likely to be used for higher
grades of VUR.We performed a retrospective review of 126 consecutive
patients with primary VUR (196 refluxing ureters) who underwent injection for
febrile urinary tract infections (UTI) to identify factors associated with
success following Dx/HA injection [13]. Endoscopic injection was performed
using both the STING and the HIT techniques in this series though neither were
prospectively planned in any patient nor systematically varied over the course
of the series. Success was defined as resolution of VUR after first injection
on postoperative VCUG performed 3 months following endoscopic treatment. Univariate
and multivariate regression analysis were performed on the following variables:
age at surgery, gender, laterality, time between presentation and surgery,
preoperative VUR grade, surgeon experience, lower urinary tract symptoms (LUTS),
and volume of Dx/HA injection. Statistical analysis was performed with SPSS version 13.0 software (SPSS Inc., Chicago,
Ill, USA), with P-values less than
.05 considered statistically significant.By renal unit,
VUR grades were as follows: I in 7(3.5%), II in 53(27%), III in 91(46.4%), IV
in 30(15.3%), and V in 15(7.6%), with a mean VUR grade of 3. Success rate after
1 injection was 50% by patient and 59.2% by ureter. Success rate by grade was
100% for grade I, 75% for grade II, 57% for grade III, 37% for grade IV, and
46% for grade V. Mean injected volume was0.9±0.27 mL in those who had a
successful injection versus 0.67±0.24 mL in those who failed (P<.001). Success after 1 injection was 78.9% using ≥0.8 mL Dx/HA
compared to 31.7% with <0.8 mL. The mean Dx/HA volume increased from 0.75±0.26 mL in the first 98 ureters treated to 0.87±0.29 mL in the last 98 (P=.002),
a change that was associated with a simultaneous improvement in the success
rate for grade III VUR from 50 to 68%. This increase in injected volume was not
prompted by an interim assessment of our results, though it can be speculated
that it may be a reflection of a change in technique form the classical STING
to the HIT (see above). However, there was no statistical difference in the
mean injected volume for high- and low-grade VUR: I–II (0.82±0.29 mL)
versus III–IV (0.78±0.26 mL),
indicating that grade did not influence injection volume across the series. The
success rates for each 0.1 mL increase in injected Dx/HA volume is plotted in
Figure 1. Our analysis showed that for each 0.1 mL increment in the injected
Dx/HA volume, a statistically significant improvement in success rate was
observed when compared to correction achieved below that cutoff volume. This
volume effect persisted up to a maximum of 1 mL injected beyond which no
further increase in success rate was observed (see discussion of  arbitrary
choice of cutoff volume in [12] above). Multivariable analysis confirmed that
higher Dx/HA volume (P=.001), lower
preoperative grade (P=.013), surgeon
experience (P=.025), and treatment of
LUTS (P=.009) were all independently
associated with successful correction of VUR.Figure 1
VUR
correction rates for each 0.1 mL increment in injected Dx/HA volume.


## 4. Can Injected Volume in Association with Obliteration of Hydrodistension Be Used in Combination to Predict Success?

The use of
mound morphology as the injection progresses as a predictor of VUR resolution
is fraught with some inherent drawbacks. What defines a “good” mound is a
subjective measure much like the subjectivity of the “good urethral plate” in
hypospadias surgery; both are qualitative, difficult to define, and are based
on surgeon experience. Secondly, the mound is a 2-dimensional view of the
effect of the injection at the ureteric orifice, but gives no indication of the
support achieved, if any, along the entire intra vesical ureter. In addition,
the mound at injection may not be the mound at the time of reassessment by a
VCUG at 3 months. There is a well-documented 19% decrease in the injected
Dx/HA bolus over 3 months [8]. This volume reduction occurs because the dextranomer
microspheres constitute 50% of the volume in Dx/HA and their hydrolysis
overtime will alter the mound morphology, likely shrinking it somewhat, notwithstanding
the stabilizing effect of collagen ingrowth [17]. This coupled with a risk of
bolus migration would mean that the surgeon could use mound morphology as a
predictor of VUR correction at the time
of injection but this endpoint may not be a stable indicator of longer term
success. In studies which showed the effect of a “favorable” mound morphology
on outcome, VUR resolved in 53% of ureters in Lavelle’s series and in 36% in
the study by Yucel et al. [11]. Moreover,
up to 12% of “good” mounds can have persistent VUR following Dx/HA injection
[18].These studies
all share the inherent limitations of nonrandomized retrospective reviews. In
the present paper, this primarily involves failure to identify and include of
all confounding variables which could impact the results. For example, one of
the criticisms of our study is that the technique of injection (HIT versus
STING) was not analyzed. Moreover, the very indications for treatment of the
reflux vary from study to study, along with the severity of VUR further confounding
the results and their comparison with other studies.


## 5. Conclusions

There are several factors which may
predict successful VUR correction following Dx/HA injection. Our study revealed
the presence of a direct association between injected volume and VUR
correction, by treating volume as a continuous variable, even while controlling
for other variables, highlighting its importance as a true success modifier. The
injected volume of Dx/HA is a factor, which to a degree under the direct
control of the surgeon. Given the
exigencies of materials cost, and the expectation on surgeons to use available
medical resources responsibly, without a clear demonstration of the effect of
volume on results, the surgeon is to a certain extent hesitant to use only a
small portion of a second Dx/HA syringe, beyond the 0.8–1 mL available for
injection in the standard commercially available syringe. Based on our
experience, we now adopt a more aggressive approach in injecting a minimum of
0.8 mL irrespective of the grade of VUR and ensure obliteration of hydrodistension
at the end of injection. From a cost stand point, an injection failure
definitely involves higher costs and, therefore, it is reasonable to use a
higher volume at the initial attempt to improve success rates. Syringes with
slightly greater volumes of 1.2–1.4 mL, should
they become available in the future, may provide greater treatment flexibility
in this regard. Finally, though endoscopic injection for VUR is generally
accepted as a simple procedure, the importance of technique and experience are evident
in most studies. Further prospective studies which include all variables, and
which possibly perform hydrodistension in a standardized manner, need to be
conducted to identify factors which can be used for patient counselling, and
increase success rates to those won by open correction of VUR.



---

*Source: 579370-2008-09-29.xml*