- Email: [email protected]
Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System
Author's Accepted Manuscript Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System Linda C. Lee , Armando J. Lorenzo , Rakan Odeh , Michelle Falkiner , Dawn-Ann Lebarron , Jeffrey Traubici , Erika Mann , Paul R. Bowlin , Martin A. Koyle
PII: DOI: Reference:
S0022-5347(16)31199-5 10.1016/j.juro.2016.08.102 JURO 13983
To appear in: The Journal of Urology Accepted Date: 15 August 2016 Please cite this article as: Lee LC, Lorenzo AJ, Odeh R, Falkiner M, Lebarron DA, Traubici J, Mann E, Bowlin PR, Koyle MA, Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.08.102. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
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Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System
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Linda C. Lee, Armando J. Lorenzo, Rakan Odeh, Michelle Falkiner, Dawn-Ann Lebarron, Jeffrey Traubici, Erika Mann, Paul R. Bowlin and Martin A. Koyle
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From the Division of Urology, Department of Surgery (LCL, AJL, RO, PRB, MAK) and Department of Radiology (MF, DAL, JT, EM), The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Corresponding Author:
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Word count: 2448 (excluding abstract and references)
Martin A. Koyle, MD, MSc, FAAP, FACS, FRCS (Eng.), FRCSC
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Chief of Paediatric Urology
The Hospital for Sick Children
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555 University Avenue, Rm M299 Toronto Ontario M5G 1X8 Canada
Email: [email protected] Phone: 416-813-6580
Key words: Voiding cystourethrography, urinary tract infection, vesicoureteral reflux, guidelines 1
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ABSTRACT Purpose: VCUG involves radiation exposure and is invasive. Several guidelines, including the AAP guidelines in 2011, no longer recommend routine VCUG after the initial UTI in children. The recent trend
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in VCUG use remains largely unknown. In this study, we examined practice patterns of VCUG use and explore the impact of these guidelines within a single-payer system over the past 8 years.
Materials and Methods: All VCUGs performed at a large pediatric referral center between January 2008
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and December 2015 were identified. Patients aged 2-24 months whom had an initial VCUG for the diagnosis of a UTI in the first 6 months of 2009 and 2014 were identified. Medical records were
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retrospectively reviewed.
Results: During the study period, a total of 8422 VCUGs were performed and the annual number of VCUGs declined over time. In the pre- and post-AAP cohorts, 233 and 95 initial VCUGs were performed, respectively. While there was no statistically significant difference in VUR detection rate between 2009 and 2014 (37.3% vs. 43.0%, p=0.45), there has been a three-fold increase in high-grade
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VUR in 2014 (2.6% vs. 8.4%, p=0.03).
Conclusions: A clear trend towards fewer VCUGS was noted at our institution. This decline started before 2011 and cannot be attributed to the AAP guidelines alone. While the majority of VUR detected
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remains low-grade, there has been a higher detection rate of high-grade VUR in 2014, compared to 2009.
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This may reflect a favorable impact of a more selective approach to obtaining VCUGs.
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INTRODUCTION Urinary tract infections (UTI) are common, affecting approximately 2% of males and 8% of females by age 7.1 Of the children who present with febrile UTIs, 25-40% are diagnosed with
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vesicoureteral reflux (VUR).2,3 The rationale for treating VUR has historically been for prevention of recurrent infections, which could incur morbidity and lead to renal scarring, hypertension and chronic kidney disease (CKD). Voiding cystourethrography (VCUG) remains the test of choice for diagnosis and grading of VUR. However, VCUG is associated with radiation exposure,4 iatrogenic UTIs,5 pain from
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catheterization, and parental and child anxiety.6,7 As the majority of VUR cases diagnosed are low-grade
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and associated with a high rate of spontaneous resolution,8 which calls into question the need for routine evaluation of children with this imaging modality. In select cases, VUR may even be managed with surveillance alone.9
Over the past decade, international guidelines have recommended more selective use of VCUG. These include the European Society for Pediatric Urology/European Association of Urology (published in
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2015)10, National Institute for Health Care Excellence (2007)11 and Canadian Paediatric Society guidelines (2015)12. The American Academy of Pediatrics (AAP) revised their guidelines in 2011 regarding the diagnosis and management of UTIs in children between 2 and 24 months. Representing a
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dramatic departure from its 1999 guidelines, the AAP no longer recommends routine VCUG following the initial febrile UTI in selected cases, most notably if the renal and bladder ultrasound (RBUS) is
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normal.13
Considering these developments, we hypothesize that there has been a downward trend in VCUG
in recent years and that the 2011 AAP guidelines have had a major impact on overall VCUG practice patterns and the severity of VUR being diagnosed. The primary aim of this paper is to examine the overall use of VCUGs performed at our institution over an 8-year period. The secondary aim was to study two representative cohorts ages 2 to 24 months who underwent an initial VCUG for the work-up of UTI before and after 2011, in order to assess the impact of the revised AAP guidelines.
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MATERIALS AND METHODS All VCUGs performed at our institution over an 8-year period (from January 1, 2008 to December 31, 2015) were identified. This included imaging studies sent for consultation, as it is our
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practice is to routinely upload tests performed elsewhere onto Picture Archiving and Communication System (PACS) for all new patients. These VCUGs were determined to be initial or repeat examinations, based on our institutional imaging database.
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In order to assess the impact of the 2011 AAP guidelines, we examined data from patients aged 2 to 24 months who had an initial VCUG for the work-up of a UTI within the first 6 months (January 1 to
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June 30) of 2009 and the same time frame in 2014 (i.e. “before-and-after” effect). The 2009 cohort was defined as the pre-AAP cohort and the 2014 cohort was defined as the post-AAP cohort. Patients presenting with isolated hydronephrosis (including antenatal), associated anomalies (e.g. MCDK), neurogenic bladder, urethral trauma and other diagnoses related to primary VUR (e.g. recurrent epididymitis) were excluded. Information was obtained from our electronic medical record regarding
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patient demographics, clinical history and other relevant imaging (such as RBUS, dimercaptosuccinic acid scan, Lasix renography). We also reviewed the indication for VCUG, specialty training of ordering physician, rate of VUR diagnosis, the presence of bilateral VUR and grade of VUR diagnosed. VUR
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grading was based on the International Reflux Study Classification.14 To reliably determine the type of ordering physician, individual practitioner names were manually inputted into a physician registry on the
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College of Physicians and Surgeons of Ontario (CPSO) website. To avoid over or underestimations of the intervention effect, we subsequently performed a time series analysis employing auto-correlated linear regression to take into account the time trend and autocorrelation among the observations.15 A two-sided Mann-Whitney test was used for continuous variables and chi-square test or Fisher’s
exact test was used for categorical variables, as appropriate. Statistical analyses were performed using Prism 7 (GraphPad, San Diego, CA) and IBM SPSS® Statistics version 23 (IBM Corporation, Armonk, NY) for autocorrelation and time trend analysis. A p-value cut-off of 0.05 was considered to be
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statistically significant. Approval was obtained from the Quality Management Committee as a Quality
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Improvement project.
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RESULTS From January 1, 2008 to December 31, 2015, a total of 8422 VCUGs were performed at our institution. Of these, 7875 (93.5%) were initial VCUGs and 547 (6.5%) were repeat VCUGs. The annual
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number of VCUGs has declined steadily over time (Figure 1), although this trend was clearly detected prior to 2011. In order to examine the impact of the 2011 AAP guidelines, we compared patients in the pre- and post-AAP cohorts (Table 1). We identified 233 and 95 initial VCUGs in these two cohorts, respectively. The indication for VCUG were determined by ordering physicians. In both cohorts,
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pediatricians account for the majority of ordering physicians. The majority of patients underwent at least one RBUS at our institution (77.7% in 2009 vs. 65.3% in 2014, where p=0.026). Among patients who
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underwent a RBUS, there was a higher proportion of patients had hydronephrosis in the post-AAP cohort (25.8% in 2014 vs. 12.2% in 2009, where p=0.015).
The detection rate of VUR was 37.3% and 43.0% in the pre- and post-AAP cohorts, respectively (p=0.45). There was a slight decrease in low-grade (I-III) VUR (34.8% in 2009 vs. 33.7% in 2014) and a
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three-fold increase in diagnosis of high grade (IV-V) VUR in the post-AAP cohort (2.6% in 2009 vs. 8.4% in 2014; p=0.03). In cases of bilateral VUR, the most severe grade of VUR was considered. These findings are summarized in Table 2.
We subsequently extracted semi-annual number of VCUGs between 2008 and 2015 (15
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computable first lags), and estimated the association between current and past series values with an
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autocorrelation function (ACF) plot. This plot (Figure 2) demonstrated a progressive decrease in positive ACF to the lag point corresponding to the timeframe around publication of the AAP guidelines, followed by negative ACF afterwards). Autocorrelation was confirmed with the Box-Ljung statistic, supporting that data are not independently distributed an exhibit serial correlation (p<0.002 for all lags). Data were then evaluated at time points before and after the publication of the AAP guidelines, exploring the presence of an effect above the underlying secular trend, with time series regression analysis. A trend for a decrease in number of VCUGs (-64.8/6 months) was noted, with a post-intervention regression line slope of -22.2. The 6 and 12-month post-intervention level effect, although consistent with a decrease in 6
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number of studies per time period, failed to show statistical significance (p=0.58 and p=0.33 respectively). Thus, when trend is taken into account, it is uncertain of publication of the AAP guidelines
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alone had an independent significant impact on the detected decrease in number of VCUGs obtained.
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DISCUSSION The perception of VUR has changed over time, from a disease in need of surgical correction to a radiographic finding of varied clinical significance. VUR has historically been associated with recurrent
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pyelonephritis, renal scarring, hypertension and CKD. This was the justification for many patients to undergo open reflux surgery. In recent years, the need for ureteral reimplantation has been called into question. An Australian study found that the incidence of reflux nephropathy did not change after the
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introduction of open reflux surgery over a 27-year period.16 Modern management of VUR is more
selective and trending towards less aggressive options, such as endoscopic treatment by subureteric
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injection, antibiotic prophylaxis, and surveillance in select low-risk patients.9 The Swedish reflux trial randomized patients with grades III-IV VUR to endoscopic treatment by subureteric injection of dextranomer/hyaluronic acid copolymer, antibiotic prophylaxis and surveillance. In this study, males did not benefit from either intervention, unlike their female counterparts.17 The RIVUR trial enrolled patients with grades I-IV VUR and randomized them to antibiotic prophylaxis or placebo. While UTI recurrence
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was reduced by 50% on prophylaxis, the rate of renal scarring was not affected. Additionally, children on antibiotic prophylaxis had a higher risk of having TMP-SMX-resistant Escherichia coli on rectal swabs.18 This may have a downstream effect on how healthcare providers view, treat and ultimately, screen for
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VUR. At mentioned previously, many international organizations recommend selective use of VCUG following an initial febrile UTI.10-13
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There is little known about how VCUG use has evolved over the past few years. The purpose of this study was to examine contemporary practice patterns in VCUG use among ordering physicians and the potential impact of the 2011 AAP guidelines. Our data show that VCUG use has been declining in recent years. However, this trend began prior to 2011. The reasons for this may be multifactorial, with the introduction of endoscopic injection for VUR therapy, the Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT)19 and Swedish reflux14 trials and National Institute for Health and Care Excellence11 guidelines, all pre-dating 2011. We anticipate that this trend will continue, given that other guidelines have followed suit and do not advocate 8
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for routine VCUG use following an initial febrile UTI in children. Not surprisingly, pediatricians comprise the majority of ordering physicians. Urologists tend to see patients once they have been diagnosed with VUR by the pediatrician and ordered only 17% of VCUGs in our study. It is still
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important for urologists to be involved in the decision-making process, given that they are able to offer the full spectrum of treatment options when necessary. With regards to radiation exposure, the As Low as Reasonably Achievable (ALARA) principle is particularly relevant in children.20 There is increasing awareness amongst families regarding the risks of radiation, in part due to campaigns such as Image
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Gently.21
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In our 2009 and 2014 cohorts, the rate of VUR diagnosis was unchanged and yet, there was a higher rate of grades IV-V VUR diagnosed in the latter group. While we are unable to attribute this to the AAP guidelines alone, it is still an interesting finding. One possibility is that the more selective use of VCUG in 2014 has led to the diagnosis of more “clinically significant” VUR. This is in contrast to the study published by Arlen et al., which found no difference in the mean maximum grade of VUR
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diagnosed in 2011 and 2012.22
To date, the revised 2011 AAP guidelines remain controversial. The RIVUR authors have since advocated to revisit the AAP’s recommendations regarding VCUG. This was based on the finding that
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antibiotic prophylaxis reduces the risk of recurrent UTI.18 The AAP guidelines also recommend that children presenting with an initial febrile UTI should have a RBUS. Although not explicitly referred to as
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a “screening” test, it is often viewed as such. One study called into question the use of RBUS upfront and reserving VCUG for those who have abnormalities on RBUS or a second febrile UTI. The authors point to a poor correlation between US abnormalities and VUR on VCUG. Instead, they suggest that RBUS and VCUG should be viewed as complementary, as they provide different radiographic information.23 Arlen et al. also note poor correlation between these two radiographic tests.22 The AAP guidelines also recommend deferring obtaining a VCUG until a second febrile UTI in the setting of a normal RBUS. The concern with this recommendation is that it may predispose children to additional febrile UTIs before VUR is diagnosed. It is concerning that Arlen et al. and our study noted a decline in VCUG and RBUS 9
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use in our post-AAP cohort,22 when one would expect a rise in RBUS use as a “screening” test. Utilization of RBUS was diminished by 7.5% in our study and further diminished by 17.2% in the study by Arlen et al. The decline in RBUS use was unexpected, as the AAP guidelines do recommend it for all
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patients between 2 and 24 months presenting with an initial febrile UTI. Furthermore, there is little known about potential negative effects of selective VCUG use. The concerns of under-diagnosis and undertreatment are also legitimate. Whether selective VCUG use would lead to downstream effects of delayed
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diagnosis and morbidity from pyelonephritis, renal insufficiency and hypertension warrants further
investigation. Our study has a number of limitations due to its retrospective nature. Some patients were
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treated in outpatient and ER settings outside of our institution and as such, we did not have access to these records. For these patients, we were unable to document how they had presented before they were diagnosed with a UTI and to differentiate between a febrile, symptomatic or even misdiagnosed UTI. Our primary aim to assess overall VCUG use at our institution lead to our cohorts being inclusive of all patients under 18 years of age and for all indications. Hence, this captures patients who underwent a
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VCUG to rule out lower urinary tract abnormalities (e.g. posterior urethral valves, urethral stricture disease) and those with secondary VUR. Our secondary aim was to comprehensively compare groups at two different time points (2009 and 2014). The limitation to this before-and-after analysis is that it fails to
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account for other factors aside from the AAP guidelines. In order to account for these confounding factors, a time-series analysis was performed and this demonstrates that the declining trend in VCUG use
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is unlikely to be related to the AAP guidelines alone. The implications of our data are broader and may reflect overall attitudes towards this fluoroscopic test among ordering physicians. Finally, our study focused on those who received one or more VCUGs at our institution. It does not take into account the number of children each year who actually presented with a febrile UTI and may have not undergone imaging. It also does not factor in the changing referral base that our institution serves each year. Despite its limitations, our study raises intriguing questions about the evolving diagnosis and management of VUR in recent years. Furthermore, these data were gathered within a single payer, universal access to care system, thus removing concerns regarding insurance and selective reimbursement 10
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from ordering practices. In the future, we plan to examine population-based data to look at how VCUG use has changed and whether this has impacted children who are diagnosed with VUR. Important outcomes include recurrent pyelonephritis, renal scarring, chronic kidney disease and reflux surgery over
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time.
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CONCLUSIONS There has been an overall trend towards fewer VCUGS being performed at our institution. Given that the rate of annual VCUGs was declining prior to 2011, this trend may be a reflection of changing
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practice patterns among ordering physicians. The revised 2011 AAP guidelines may have played a role but was clearly not the only factor. While the majority of VUR cases detected remain low-grade, there has been a higher detection rate of high-grade (IV-V) VUR in 2014, compared to 2009. This may reflect a
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trend towards detection of more “clinically significant” VUR.
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REFERENCES 1. Hellström A, Hanson E, Hansson S et al: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991; 66, 232.
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2. Greenfield SP and Wan J: Vesicoureteral reflux: practical aspects of evaluation and management. Pediatr Nephrol 1996; 10, 789.
3. Hellerstein S: Urinary tract infections. Old and new concepts. Pediatr Clin North Am 1995; 42,
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1433.
4. La Scola C, De Mutiis C, Hewitt IK et al: Different Guidelines for Imaging After First UTI in
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Febrile Infants: Yield, Cost, and Radiation. Pediatrics 2013; 131, e665.
5. Rachmiel M, Aladjem M, Starinsky R et al: Symptomatic urinary tract infections following voiding cystourethrography. Pediatr Nephrol 2005; 20, 1449.
6. Lachenmyer LL, Anderson JJ, Clayton DB et al: Analysis of an intervention to reduce parental anxiety prior to voiding cystourethrogram. J Pediatr Urol 2013; 9, 1223.
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7. Srivastava T, Betts G, Rosenberg AR et al: Perception of fear, distress and pain by parents of children undergoing a micturating cystourethrogram: a prospective study. J Paediatr Child Health 2001; 37, 271.
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8. Estrada CR Jr, Passerotti CC, Graham DA et al: Nomograms for Predicting Annual Resolution Rate of Primary Vesicoureteral Reflux: Results From 2,462 Children. J Urol 2009; 182, 1535.
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9. Peters CA, Skoog SJ, Arant BS Jr et al: Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol 2010; 184, 1134.
10. Stein R, Dogan HS, Hoebeke P et al: Urinary Tract Infections in Children: EAU/ESPU Guidelines. Eur Urol 2015; 67, 546.
11. National Institute of Health and Clinical Excellence: Urinary tract infection in children: diagnosis, treatment and long-term management. RCOG Press 2007.
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12. Robinson JL, Finlay JC, Lang ME et al: Urinary tract infections in infants and children: Diagnosis and management. Paediatr Child Health 2014; 19, 315. 13. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and
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Management: Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months. Pediatrics 2011; 128, 595.
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14. International Reflux Study Committee: Medical versus surgical treatment of primary
vesicoureteral reflux: a prospective international reflux study in children. J Urol 1981; 125, 277.
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15. Effective Practice and Organisation of Care (EPOC). EPOC Resources for review authors. Oslo: Norwegian Knowledge Centre for the Health Services; 2015. Available at: http://epoc.cochrane.org/epoc-specific-resources-review-authors
16. Craig JC, Irwig LM, Knight JF, et al. Does treatment of vesicoureteral reflux in childhood prevent end-stage renal disease attributable to reflux nephropathy? Pediatrics 2000;105,1236.
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17. Brandström P, Jodal U, Sillén U et al: The Swedish reflux trial: Review of a randomized, controlled trial in children with dilating vesicoureteral reflux. J Pediatr Urol 2011; 7, 594. 18. The RIVUR Trial Investigators: Antimicrobial Prophylaxis for Children with Vesicoureteral
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Reflux. N Engl J Med 2014; 370, 2367.
19. Craig JC, Simpson JM, Williams GJ et al: Antibiotic prophylaxis and recurrent urinary tract
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infection in children. N Engl J Med 2009; 361, 1748. 20. Lee RS, Diamond DA and Chow JS. Applying the ALARA concept to the evaluation of vesicoureteric reflux. Pediatr Radiol 2006; 36, 185.
21. The Alliance for Radiation Safety in Pediatric Imaging (2016, May 20). Image Gently. Retrieved from http://www.imagegently.org 22. Arlen AM, Merriman LS, Kirsch JM et al: Early Effect of American Academy of Pediatrics Urinary Tract Infection Guidelines on radiographic imaging and diagnosis of vesicoureteral reflux in the emergency room setting. J Urol 2015; 193, 1760. 14
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23. Nelson CP, Johnson EK, Logvinenko T et al: Ultrasound as a Screening Test for Genitourinary
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Anomalies in Children With UTI. Pediatrics 2014; 133, e394.
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Table 1: Patient and ordering physician characteristics for patients between 2 to 24 months presenting with a UTI 2014 cohort (n=95) 8.8 +/- 6.5
98 (42.1%) 135 (57.9%) 188 (77.7%) 22 (12.2%)
52 (54.7%) 43 (45.3%) 62 (65.3%) 16 (25.8%)
0.039
6 (6.3%) 77 (81.1%) 4 (4.2%) 0 (0.0%) 8 (8.4%)
0.026
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0.78
0.026 0.015
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21 (9.0%) 182 (78.1%) 21 (9.0%) 4 (1.7%) 5 (2.1%)
p-value
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Mean age, in months +/- SD Sex Male (%) Female (%) No. RBUS (%) Hydronephrosis on RBUS (%) Ordering physician Urologist (%) Pediatrician (%) General practitioner (%) Other (%) Unknown (%)
2009 cohort (n=233) 9.1 +/- 6.2
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Table 2: Voiding cystourethrography findings
81 (34.8%) 6 (2.6%)
32 (33.7%) 8 (8.4%)
p-value 0.45 0.61 0.67
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2014 cohort (n=95) 40 (43.0%) 15 (15.8%) 25 (26.3%)
0.90 0.03
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VUR diagnosis Unilateral (%) Bilateral (%) Maximum VUR grade Low grade, I-III (%) High grade, IV-V (%)
2009 cohort (n=233) 87 (37.3%) 32 (13.7%) 55 (23.6%)
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Figure 1: Annual number of VCUGs from 2008 to 2015 2000 1800 Initial
1400
Repeat
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1600
1200 1000 800
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600 400
0 2008
2009
2010
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200 2011
2012
2013
2014
2015
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Year
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Figure 2: Autocorrelation function plot for semi-annual (i.e. 6 month intervals) VCUGs performed between 2008 and 2015.
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ABBREVIATIONS AND ACRONYMS AAP = American Academy of Pediatrics RBUS = renal and bladder ultrasound
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UTI = urinary tract infection VCUG = voiding cystourethrogram
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VUR = vesicoureteral reflux
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PII: DOI: Reference:
S0022-5347(16)31199-5 10.1016/j.juro.2016.08.102 JURO 13983
To appear in: The Journal of Urology Accepted Date: 15 August 2016 Please cite this article as: Lee LC, Lorenzo AJ, Odeh R, Falkiner M, Lebarron DA, Traubici J, Mann E, Bowlin PR, Koyle MA, Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System, The Journal of Urology® (2016), doi: 10.1016/j.juro.2016.08.102. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
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Contemporary Practice Patterns of Voiding Cystourethrography Use at a Large Tertiary Care Center in a Single Payer Health Care System
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Linda C. Lee, Armando J. Lorenzo, Rakan Odeh, Michelle Falkiner, Dawn-Ann Lebarron, Jeffrey Traubici, Erika Mann, Paul R. Bowlin and Martin A. Koyle
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From the Division of Urology, Department of Surgery (LCL, AJL, RO, PRB, MAK) and Department of Radiology (MF, DAL, JT, EM), The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Corresponding Author:
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Word count: 2448 (excluding abstract and references)
Martin A. Koyle, MD, MSc, FAAP, FACS, FRCS (Eng.), FRCSC
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Chief of Paediatric Urology
The Hospital for Sick Children
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555 University Avenue, Rm M299 Toronto Ontario M5G 1X8 Canada
Email: [email protected] Phone: 416-813-6580
Key words: Voiding cystourethrography, urinary tract infection, vesicoureteral reflux, guidelines 1
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ABSTRACT Purpose: VCUG involves radiation exposure and is invasive. Several guidelines, including the AAP guidelines in 2011, no longer recommend routine VCUG after the initial UTI in children. The recent trend
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in VCUG use remains largely unknown. In this study, we examined practice patterns of VCUG use and explore the impact of these guidelines within a single-payer system over the past 8 years.
Materials and Methods: All VCUGs performed at a large pediatric referral center between January 2008
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and December 2015 were identified. Patients aged 2-24 months whom had an initial VCUG for the diagnosis of a UTI in the first 6 months of 2009 and 2014 were identified. Medical records were
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retrospectively reviewed.
Results: During the study period, a total of 8422 VCUGs were performed and the annual number of VCUGs declined over time. In the pre- and post-AAP cohorts, 233 and 95 initial VCUGs were performed, respectively. While there was no statistically significant difference in VUR detection rate between 2009 and 2014 (37.3% vs. 43.0%, p=0.45), there has been a three-fold increase in high-grade
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VUR in 2014 (2.6% vs. 8.4%, p=0.03).
Conclusions: A clear trend towards fewer VCUGS was noted at our institution. This decline started before 2011 and cannot be attributed to the AAP guidelines alone. While the majority of VUR detected
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remains low-grade, there has been a higher detection rate of high-grade VUR in 2014, compared to 2009.
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This may reflect a favorable impact of a more selective approach to obtaining VCUGs.
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INTRODUCTION Urinary tract infections (UTI) are common, affecting approximately 2% of males and 8% of females by age 7.1 Of the children who present with febrile UTIs, 25-40% are diagnosed with
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vesicoureteral reflux (VUR).2,3 The rationale for treating VUR has historically been for prevention of recurrent infections, which could incur morbidity and lead to renal scarring, hypertension and chronic kidney disease (CKD). Voiding cystourethrography (VCUG) remains the test of choice for diagnosis and grading of VUR. However, VCUG is associated with radiation exposure,4 iatrogenic UTIs,5 pain from
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catheterization, and parental and child anxiety.6,7 As the majority of VUR cases diagnosed are low-grade
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and associated with a high rate of spontaneous resolution,8 which calls into question the need for routine evaluation of children with this imaging modality. In select cases, VUR may even be managed with surveillance alone.9
Over the past decade, international guidelines have recommended more selective use of VCUG. These include the European Society for Pediatric Urology/European Association of Urology (published in
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2015)10, National Institute for Health Care Excellence (2007)11 and Canadian Paediatric Society guidelines (2015)12. The American Academy of Pediatrics (AAP) revised their guidelines in 2011 regarding the diagnosis and management of UTIs in children between 2 and 24 months. Representing a
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dramatic departure from its 1999 guidelines, the AAP no longer recommends routine VCUG following the initial febrile UTI in selected cases, most notably if the renal and bladder ultrasound (RBUS) is
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normal.13
Considering these developments, we hypothesize that there has been a downward trend in VCUG
in recent years and that the 2011 AAP guidelines have had a major impact on overall VCUG practice patterns and the severity of VUR being diagnosed. The primary aim of this paper is to examine the overall use of VCUGs performed at our institution over an 8-year period. The secondary aim was to study two representative cohorts ages 2 to 24 months who underwent an initial VCUG for the work-up of UTI before and after 2011, in order to assess the impact of the revised AAP guidelines.
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MATERIALS AND METHODS All VCUGs performed at our institution over an 8-year period (from January 1, 2008 to December 31, 2015) were identified. This included imaging studies sent for consultation, as it is our
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practice is to routinely upload tests performed elsewhere onto Picture Archiving and Communication System (PACS) for all new patients. These VCUGs were determined to be initial or repeat examinations, based on our institutional imaging database.
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In order to assess the impact of the 2011 AAP guidelines, we examined data from patients aged 2 to 24 months who had an initial VCUG for the work-up of a UTI within the first 6 months (January 1 to
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June 30) of 2009 and the same time frame in 2014 (i.e. “before-and-after” effect). The 2009 cohort was defined as the pre-AAP cohort and the 2014 cohort was defined as the post-AAP cohort. Patients presenting with isolated hydronephrosis (including antenatal), associated anomalies (e.g. MCDK), neurogenic bladder, urethral trauma and other diagnoses related to primary VUR (e.g. recurrent epididymitis) were excluded. Information was obtained from our electronic medical record regarding
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patient demographics, clinical history and other relevant imaging (such as RBUS, dimercaptosuccinic acid scan, Lasix renography). We also reviewed the indication for VCUG, specialty training of ordering physician, rate of VUR diagnosis, the presence of bilateral VUR and grade of VUR diagnosed. VUR
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grading was based on the International Reflux Study Classification.14 To reliably determine the type of ordering physician, individual practitioner names were manually inputted into a physician registry on the
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College of Physicians and Surgeons of Ontario (CPSO) website. To avoid over or underestimations of the intervention effect, we subsequently performed a time series analysis employing auto-correlated linear regression to take into account the time trend and autocorrelation among the observations.15 A two-sided Mann-Whitney test was used for continuous variables and chi-square test or Fisher’s
exact test was used for categorical variables, as appropriate. Statistical analyses were performed using Prism 7 (GraphPad, San Diego, CA) and IBM SPSS® Statistics version 23 (IBM Corporation, Armonk, NY) for autocorrelation and time trend analysis. A p-value cut-off of 0.05 was considered to be
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statistically significant. Approval was obtained from the Quality Management Committee as a Quality
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Improvement project.
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RESULTS From January 1, 2008 to December 31, 2015, a total of 8422 VCUGs were performed at our institution. Of these, 7875 (93.5%) were initial VCUGs and 547 (6.5%) were repeat VCUGs. The annual
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number of VCUGs has declined steadily over time (Figure 1), although this trend was clearly detected prior to 2011. In order to examine the impact of the 2011 AAP guidelines, we compared patients in the pre- and post-AAP cohorts (Table 1). We identified 233 and 95 initial VCUGs in these two cohorts, respectively. The indication for VCUG were determined by ordering physicians. In both cohorts,
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pediatricians account for the majority of ordering physicians. The majority of patients underwent at least one RBUS at our institution (77.7% in 2009 vs. 65.3% in 2014, where p=0.026). Among patients who
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underwent a RBUS, there was a higher proportion of patients had hydronephrosis in the post-AAP cohort (25.8% in 2014 vs. 12.2% in 2009, where p=0.015).
The detection rate of VUR was 37.3% and 43.0% in the pre- and post-AAP cohorts, respectively (p=0.45). There was a slight decrease in low-grade (I-III) VUR (34.8% in 2009 vs. 33.7% in 2014) and a
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three-fold increase in diagnosis of high grade (IV-V) VUR in the post-AAP cohort (2.6% in 2009 vs. 8.4% in 2014; p=0.03). In cases of bilateral VUR, the most severe grade of VUR was considered. These findings are summarized in Table 2.
We subsequently extracted semi-annual number of VCUGs between 2008 and 2015 (15
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computable first lags), and estimated the association between current and past series values with an
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autocorrelation function (ACF) plot. This plot (Figure 2) demonstrated a progressive decrease in positive ACF to the lag point corresponding to the timeframe around publication of the AAP guidelines, followed by negative ACF afterwards). Autocorrelation was confirmed with the Box-Ljung statistic, supporting that data are not independently distributed an exhibit serial correlation (p<0.002 for all lags). Data were then evaluated at time points before and after the publication of the AAP guidelines, exploring the presence of an effect above the underlying secular trend, with time series regression analysis. A trend for a decrease in number of VCUGs (-64.8/6 months) was noted, with a post-intervention regression line slope of -22.2. The 6 and 12-month post-intervention level effect, although consistent with a decrease in 6
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number of studies per time period, failed to show statistical significance (p=0.58 and p=0.33 respectively). Thus, when trend is taken into account, it is uncertain of publication of the AAP guidelines
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alone had an independent significant impact on the detected decrease in number of VCUGs obtained.
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DISCUSSION The perception of VUR has changed over time, from a disease in need of surgical correction to a radiographic finding of varied clinical significance. VUR has historically been associated with recurrent
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pyelonephritis, renal scarring, hypertension and CKD. This was the justification for many patients to undergo open reflux surgery. In recent years, the need for ureteral reimplantation has been called into question. An Australian study found that the incidence of reflux nephropathy did not change after the
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introduction of open reflux surgery over a 27-year period.16 Modern management of VUR is more
selective and trending towards less aggressive options, such as endoscopic treatment by subureteric
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injection, antibiotic prophylaxis, and surveillance in select low-risk patients.9 The Swedish reflux trial randomized patients with grades III-IV VUR to endoscopic treatment by subureteric injection of dextranomer/hyaluronic acid copolymer, antibiotic prophylaxis and surveillance. In this study, males did not benefit from either intervention, unlike their female counterparts.17 The RIVUR trial enrolled patients with grades I-IV VUR and randomized them to antibiotic prophylaxis or placebo. While UTI recurrence
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was reduced by 50% on prophylaxis, the rate of renal scarring was not affected. Additionally, children on antibiotic prophylaxis had a higher risk of having TMP-SMX-resistant Escherichia coli on rectal swabs.18 This may have a downstream effect on how healthcare providers view, treat and ultimately, screen for
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VUR. At mentioned previously, many international organizations recommend selective use of VCUG following an initial febrile UTI.10-13
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There is little known about how VCUG use has evolved over the past few years. The purpose of this study was to examine contemporary practice patterns in VCUG use among ordering physicians and the potential impact of the 2011 AAP guidelines. Our data show that VCUG use has been declining in recent years. However, this trend began prior to 2011. The reasons for this may be multifactorial, with the introduction of endoscopic injection for VUR therapy, the Prevention of Recurrent Urinary Tract Infection in Children with Vesicoureteric Reflux and Normal Renal Tracts (PRIVENT)19 and Swedish reflux14 trials and National Institute for Health and Care Excellence11 guidelines, all pre-dating 2011. We anticipate that this trend will continue, given that other guidelines have followed suit and do not advocate 8
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for routine VCUG use following an initial febrile UTI in children. Not surprisingly, pediatricians comprise the majority of ordering physicians. Urologists tend to see patients once they have been diagnosed with VUR by the pediatrician and ordered only 17% of VCUGs in our study. It is still
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important for urologists to be involved in the decision-making process, given that they are able to offer the full spectrum of treatment options when necessary. With regards to radiation exposure, the As Low as Reasonably Achievable (ALARA) principle is particularly relevant in children.20 There is increasing awareness amongst families regarding the risks of radiation, in part due to campaigns such as Image
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Gently.21
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In our 2009 and 2014 cohorts, the rate of VUR diagnosis was unchanged and yet, there was a higher rate of grades IV-V VUR diagnosed in the latter group. While we are unable to attribute this to the AAP guidelines alone, it is still an interesting finding. One possibility is that the more selective use of VCUG in 2014 has led to the diagnosis of more “clinically significant” VUR. This is in contrast to the study published by Arlen et al., which found no difference in the mean maximum grade of VUR
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diagnosed in 2011 and 2012.22
To date, the revised 2011 AAP guidelines remain controversial. The RIVUR authors have since advocated to revisit the AAP’s recommendations regarding VCUG. This was based on the finding that
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antibiotic prophylaxis reduces the risk of recurrent UTI.18 The AAP guidelines also recommend that children presenting with an initial febrile UTI should have a RBUS. Although not explicitly referred to as
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a “screening” test, it is often viewed as such. One study called into question the use of RBUS upfront and reserving VCUG for those who have abnormalities on RBUS or a second febrile UTI. The authors point to a poor correlation between US abnormalities and VUR on VCUG. Instead, they suggest that RBUS and VCUG should be viewed as complementary, as they provide different radiographic information.23 Arlen et al. also note poor correlation between these two radiographic tests.22 The AAP guidelines also recommend deferring obtaining a VCUG until a second febrile UTI in the setting of a normal RBUS. The concern with this recommendation is that it may predispose children to additional febrile UTIs before VUR is diagnosed. It is concerning that Arlen et al. and our study noted a decline in VCUG and RBUS 9
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use in our post-AAP cohort,22 when one would expect a rise in RBUS use as a “screening” test. Utilization of RBUS was diminished by 7.5% in our study and further diminished by 17.2% in the study by Arlen et al. The decline in RBUS use was unexpected, as the AAP guidelines do recommend it for all
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patients between 2 and 24 months presenting with an initial febrile UTI. Furthermore, there is little known about potential negative effects of selective VCUG use. The concerns of under-diagnosis and undertreatment are also legitimate. Whether selective VCUG use would lead to downstream effects of delayed
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diagnosis and morbidity from pyelonephritis, renal insufficiency and hypertension warrants further
investigation. Our study has a number of limitations due to its retrospective nature. Some patients were
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treated in outpatient and ER settings outside of our institution and as such, we did not have access to these records. For these patients, we were unable to document how they had presented before they were diagnosed with a UTI and to differentiate between a febrile, symptomatic or even misdiagnosed UTI. Our primary aim to assess overall VCUG use at our institution lead to our cohorts being inclusive of all patients under 18 years of age and for all indications. Hence, this captures patients who underwent a
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VCUG to rule out lower urinary tract abnormalities (e.g. posterior urethral valves, urethral stricture disease) and those with secondary VUR. Our secondary aim was to comprehensively compare groups at two different time points (2009 and 2014). The limitation to this before-and-after analysis is that it fails to
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account for other factors aside from the AAP guidelines. In order to account for these confounding factors, a time-series analysis was performed and this demonstrates that the declining trend in VCUG use
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is unlikely to be related to the AAP guidelines alone. The implications of our data are broader and may reflect overall attitudes towards this fluoroscopic test among ordering physicians. Finally, our study focused on those who received one or more VCUGs at our institution. It does not take into account the number of children each year who actually presented with a febrile UTI and may have not undergone imaging. It also does not factor in the changing referral base that our institution serves each year. Despite its limitations, our study raises intriguing questions about the evolving diagnosis and management of VUR in recent years. Furthermore, these data were gathered within a single payer, universal access to care system, thus removing concerns regarding insurance and selective reimbursement 10
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from ordering practices. In the future, we plan to examine population-based data to look at how VCUG use has changed and whether this has impacted children who are diagnosed with VUR. Important outcomes include recurrent pyelonephritis, renal scarring, chronic kidney disease and reflux surgery over
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time.
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CONCLUSIONS There has been an overall trend towards fewer VCUGS being performed at our institution. Given that the rate of annual VCUGs was declining prior to 2011, this trend may be a reflection of changing
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practice patterns among ordering physicians. The revised 2011 AAP guidelines may have played a role but was clearly not the only factor. While the majority of VUR cases detected remain low-grade, there has been a higher detection rate of high-grade (IV-V) VUR in 2014, compared to 2009. This may reflect a
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trend towards detection of more “clinically significant” VUR.
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REFERENCES 1. Hellström A, Hanson E, Hansson S et al: Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991; 66, 232.
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2. Greenfield SP and Wan J: Vesicoureteral reflux: practical aspects of evaluation and management. Pediatr Nephrol 1996; 10, 789.
3. Hellerstein S: Urinary tract infections. Old and new concepts. Pediatr Clin North Am 1995; 42,
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1433.
4. La Scola C, De Mutiis C, Hewitt IK et al: Different Guidelines for Imaging After First UTI in
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Febrile Infants: Yield, Cost, and Radiation. Pediatrics 2013; 131, e665.
5. Rachmiel M, Aladjem M, Starinsky R et al: Symptomatic urinary tract infections following voiding cystourethrography. Pediatr Nephrol 2005; 20, 1449.
6. Lachenmyer LL, Anderson JJ, Clayton DB et al: Analysis of an intervention to reduce parental anxiety prior to voiding cystourethrogram. J Pediatr Urol 2013; 9, 1223.
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7. Srivastava T, Betts G, Rosenberg AR et al: Perception of fear, distress and pain by parents of children undergoing a micturating cystourethrogram: a prospective study. J Paediatr Child Health 2001; 37, 271.
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8. Estrada CR Jr, Passerotti CC, Graham DA et al: Nomograms for Predicting Annual Resolution Rate of Primary Vesicoureteral Reflux: Results From 2,462 Children. J Urol 2009; 182, 1535.
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9. Peters CA, Skoog SJ, Arant BS Jr et al: Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol 2010; 184, 1134.
10. Stein R, Dogan HS, Hoebeke P et al: Urinary Tract Infections in Children: EAU/ESPU Guidelines. Eur Urol 2015; 67, 546.
11. National Institute of Health and Clinical Excellence: Urinary tract infection in children: diagnosis, treatment and long-term management. RCOG Press 2007.
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12. Robinson JL, Finlay JC, Lang ME et al: Urinary tract infections in infants and children: Diagnosis and management. Paediatr Child Health 2014; 19, 315. 13. Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and
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Management: Urinary Tract Infection: Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2 to 24 Months. Pediatrics 2011; 128, 595.
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14. International Reflux Study Committee: Medical versus surgical treatment of primary
vesicoureteral reflux: a prospective international reflux study in children. J Urol 1981; 125, 277.
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15. Effective Practice and Organisation of Care (EPOC). EPOC Resources for review authors. Oslo: Norwegian Knowledge Centre for the Health Services; 2015. Available at: http://epoc.cochrane.org/epoc-specific-resources-review-authors
16. Craig JC, Irwig LM, Knight JF, et al. Does treatment of vesicoureteral reflux in childhood prevent end-stage renal disease attributable to reflux nephropathy? Pediatrics 2000;105,1236.
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17. Brandström P, Jodal U, Sillén U et al: The Swedish reflux trial: Review of a randomized, controlled trial in children with dilating vesicoureteral reflux. J Pediatr Urol 2011; 7, 594. 18. The RIVUR Trial Investigators: Antimicrobial Prophylaxis for Children with Vesicoureteral
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Reflux. N Engl J Med 2014; 370, 2367.
19. Craig JC, Simpson JM, Williams GJ et al: Antibiotic prophylaxis and recurrent urinary tract
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infection in children. N Engl J Med 2009; 361, 1748. 20. Lee RS, Diamond DA and Chow JS. Applying the ALARA concept to the evaluation of vesicoureteric reflux. Pediatr Radiol 2006; 36, 185.
21. The Alliance for Radiation Safety in Pediatric Imaging (2016, May 20). Image Gently. Retrieved from http://www.imagegently.org 22. Arlen AM, Merriman LS, Kirsch JM et al: Early Effect of American Academy of Pediatrics Urinary Tract Infection Guidelines on radiographic imaging and diagnosis of vesicoureteral reflux in the emergency room setting. J Urol 2015; 193, 1760. 14
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23. Nelson CP, Johnson EK, Logvinenko T et al: Ultrasound as a Screening Test for Genitourinary
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Anomalies in Children With UTI. Pediatrics 2014; 133, e394.
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Table 1: Patient and ordering physician characteristics for patients between 2 to 24 months presenting with a UTI 2014 cohort (n=95) 8.8 +/- 6.5
98 (42.1%) 135 (57.9%) 188 (77.7%) 22 (12.2%)
52 (54.7%) 43 (45.3%) 62 (65.3%) 16 (25.8%)
0.039
6 (6.3%) 77 (81.1%) 4 (4.2%) 0 (0.0%) 8 (8.4%)
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0.026 0.015
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21 (9.0%) 182 (78.1%) 21 (9.0%) 4 (1.7%) 5 (2.1%)
p-value
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Mean age, in months +/- SD Sex Male (%) Female (%) No. RBUS (%) Hydronephrosis on RBUS (%) Ordering physician Urologist (%) Pediatrician (%) General practitioner (%) Other (%) Unknown (%)
2009 cohort (n=233) 9.1 +/- 6.2
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Table 2: Voiding cystourethrography findings
81 (34.8%) 6 (2.6%)
32 (33.7%) 8 (8.4%)
p-value 0.45 0.61 0.67
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2014 cohort (n=95) 40 (43.0%) 15 (15.8%) 25 (26.3%)
0.90 0.03
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VUR diagnosis Unilateral (%) Bilateral (%) Maximum VUR grade Low grade, I-III (%) High grade, IV-V (%)
2009 cohort (n=233) 87 (37.3%) 32 (13.7%) 55 (23.6%)
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Figure 1: Annual number of VCUGs from 2008 to 2015 2000 1800 Initial
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Repeat
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1200 1000 800
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0 2008
2009
2010
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2013
2014
2015
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Figure 2: Autocorrelation function plot for semi-annual (i.e. 6 month intervals) VCUGs performed between 2008 and 2015.
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ABBREVIATIONS AND ACRONYMS AAP = American Academy of Pediatrics RBUS = renal and bladder ultrasound
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UTI = urinary tract infection VCUG = voiding cystourethrogram
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VUR = vesicoureteral reflux
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