1、VUR, UTI, and Antibiotic Prophylaxis How to Use an Article About Therapy or Prevention,Journal Club Amy K Evans PGY2 August 15, 2006,The Case,Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acut
2、e pyelonephritis.,The Case,Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course.,T
3、he Case,Kali is a 14mo female who presents to WRAMC ED with fever to 102. Your stellar Peds Intern suggests obtaining a UA/UCx, which results in the diagnosis of acute pyelonephritis. Kali is admitted to Wd51 for 48hrs of IV abx, then, afebrile, discharged to complete po course. She undergoes renal
4、US and VCUG 3 weeks later, which reveal grade II VUR on the left.,The Question,Should we treat her prophylactically?Short-term: Will this decrease recurrent infections? Long-term: Will this decrease renal scarring? Why else would it matter?,Background,Vesicoureteral Reflux (VUR) Primary congenital i
5、ncompetence of VU valve (shortened submucosal tunnel) Secondary multiple anatomic abnormalities,Background,Incidence 1-10% Siblings 30-45% (3/4 asymptomatic) Diagnosed via VCUG UTI workup 40% (girls); 70% (infants 1yo) Antenatal hydronephrosis 9% (boys) Why worry? VUR pyelonephritis renal scarring H
6、TN, renal insufficiency, ESRD, pre-eclampsia,Background,Natural hx of VUR: spontaneous resolutionUTI VUR? VUR UTI? VUR Pyelo? VUR Scarring?,Current Treatment Recs,Workup: Febrile UTI (any age) UTI 5yo UTI x2 in school-age girls UTI in any boyTo treat or not to treat?,Imaging: Renal US 40% sensitive
7、(VUR) VCUG Diagnostic! DMSA,AUA Treatment Guidelines,Current Treatment Recs,AUA Pediatric VUR Guidelines Panel (1997) “The panel recommendations to offer continuous abx prophylaxisare based on limited scientific evidence. To our knowledge controlled studies comparing the efficacy of continuous proph
8、ylaxis and intermittent therapy on health outcomeshave not been performed.”No controlled studies? Then what are we basing treatment on?,The State of the Art,Williams et.al. (2001) Systematic review of RCTs on UTI/abx prophy Five trials, 1968-1978 Best 2: 71 patients total, normal anatomy, 92% girls
9、Garin et.al. (1998) UTI VUR? no VUR Pyelo? VUR UTI? no Degree VUR Scars? VUR Scarring? no,We Need A Study That,Will help us decide whether or not to prophylax this patientIncludes patients with symptomatic VUR Compares antibiotic prophylaxis to a control Looks at clinically important outcomes,Clinic
10、al significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study.,Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Pediatrics 2006;117:626-632.,Study Questions,Does VUR correlate with UT
11、I/renal scarring?Does antibiotic prophylaxis correlate with UTI/renal scarring?,Study Design,Randomized, controlled, multicenter trial Inclusion: 3mo-18yo Acute pyelonephritis Exclusion: Grade IV-V VUR Anatomic abnormalities Pregnancy,Study Design,Met inclusion criteria VCUGPyelo treated: IV abx po
12、for 14-day course Abx: TMP/SMX or nitrofurantoin for 1 year,VUR,No VUR,Abx,Abx,No Abx,No Abx,Follow Up,At entry: UA/UCx, DMSA, VCUG, Renal US At Q3mo clinic visit: UA/UCx At 6mo: DMSA At 12mo: VCUG, Renal USEndpoints: Recurrent UTI Renal scarring,Study Results,Analysis of Results,Fishers Exact Test
13、2x2 comparison tables Control vs. variable Smaller sample size Gives p value Does not give CIGoal: p.05!,http:/www.childrensmercy.org/stats/ask/fishers.asp,Study Results,Recurrence of UTIs Timing Type Recurrent Pyelonephritis & Antibiotics Recurrent Pyelonephritis & VUR Degree Renal Scarring VUR Ant
14、ibiotics,Study Results,Recurrence of UTI Overall 20.1% VUR not significant No abx (p=.9999) VUR 22.4% No VUR 23.3% Abx (p=0.633) VUR 23.6% No VUR 8.8%,Type of Recurrence Cystitis (no p value) VUR 8.6% No VUR 13.3% Pyelonephritis (p=.3781) VUR 7.1% No VUR 3.8%,Study Results,Recurrent Pyelo and Antibi
15、otics No benefit of abx (p=.0291) 7:1 abx:noneRecurrent Pyelo and VUR Degree 6/8 Grade III (cystitis: 46%) 2/8 Grade II (cystitis: 40%) 4/4 pts without VUR,Study Results,Renal Scarring No evidence VUR increased scarring (p=.9999)VUR (6.2%) = No VUR (5.7%) Abx (7.0%) = No Abx (5.1%)Grade I VUR 5.3% w
16、ith scars Grade II VUR 5.2% Grade III VUR 13.5%,Study Conclusions,Mild/moderate VUR not associated with UTI, pyelonephritis, or scarringAntibiotic prophylaxis not associated with UTI, pyeloneprhitis, or scarring,Critically Evaluating (JAMA Users Guide),Are the results valid? What were the results? W
17、ill the results help me to take care of my patient?,Are the results valid? Primary Guides,Was the assignment of patients to treatment randomized? YES. Were all who entered the study accounted for? Was follow-up complete? NO. Enrolled 236, lost 18 Lost from what groups? Would this change results? Wer
18、e patients analyzed in the groups assigned to? NO. Exclusion of noncompliants,Are the results valid? Secondary Guides,Were pts, clinicians, no placebos) Were groups similar at start, & treated equally? YES (age, gender, degree of reflux),What were the results?,How large was the treatment effect? ARR
19、 risk difference of variable vs. control RRR variable reduced risk by Z% relative to that occurring in control patients; bigger = better!For example, in presence of VUR: 23.6% of those on abx developed UTI (X%) 22.4% without abx developed UTI (Y%) ARR = X-Y = .236-.224 = .012 RRR = (1-Y/X)x100% = (1
20、-.224/.236)x100% = 5.1%,What were the results?,How large was the treatment effect? ARR/RRR not reported!How precise was the estimated treatment effect? Confidence Intervals (CIs) not reported! 95% CI: Range that includes the true RRR 95% of time Positive? Negative? Zero? Statistically vs. clinically
21、 significant results,What were the results?,POWER! Ability of a study to detect a true difference Directly related to sample size 1- ( = type II error)Study powered to detect a clinically significant difference of 20% (power 80%), 95% CI Need 60/group = 240 subjects Enrolled 236, Completed 218“POWER
22、 : research design : SENSITIVITY : diagnostic test”,Will the results help me take care of my patient?,Can the results be applied? YES. Could Kali have been enrolled? All clinically important outcomes considered? YES. Substitute endpoints vs. “POEMS” Adverse effects on other outcomes Are likely benef
23、its worth potential harms/risks? NNT = 1/ARR Consider baseline risk without intervention,Criticisms: Study Population,What about 3mo? Present earlier = Higher-grade reflux? Already abx? Included in study? Exclusion of noncompliants? Exclusion of pyelonephritis x2? Initial presentation with cystitis?
24、 Febrile UTI without DMSA changes? How many therefore excluded?,Criticisms: Study Design,DMSA as inclusion criteria (multicenter)? Account for 18 lost before study end? Unknown prognostic factors Recalculate results assuming they did well/poorly Blinding of patients/personnel? Placebo Diagnosis Larg
25、er sample size?,Criticisms: Data Analysis,Reporting of CIs, ARR/RRR? Magnitude/precision of treatment effect Rule in/out effect different from Ho Data crunching using Chi-Square? Different data combinations? Did not achieve POWER,Further Questions,UTI prophylaxis vs. intermittent therapy? And risk o
26、f renal scarring Over time, given resolution VUR Larger sample size VUR in context of abnormal anatomy? Mechanism of scarring in pyelonephritis? What else?,Back to our patient,What would you do?Call Dr.Cartwright and Dr.Lechner and get those patients enrolled!,References,Atala A, Keating MA. Vesicou
27、reteral reflux and megaureter. In Campbells Urology Vol 2, 7th ed. Philadelphia: WB Saunders 1988. Behrman Re, Kliegman RB, Jenson HB. Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004. Biggi A et.al. Prognostic value of the acute DMSA scan in children with first urinary tract inf
28、ection. Pediatr Nephrol 2001;16:800-804. Bjorgvinsson E, Majd M, Eggli KD. Diagnosis of acute pyelonephritis in children: comparison of sonography and 99mTc-DMSA scintigraphy. Am J Roentgenol 1991;157(3):539-543. Dawson B, Trapp RG. Basic and clinical biostatistics, 3rd ed. New York: Lange Medical B
29、ooks 2001. DeSadeeler C et.al. A multicenter trial on interobserver reproducibility in reporting on 99mTc-DMSA planer scintigraphy: a Belgian survey. J Nucl Med 2000;41(1):23-26. Elder JS et.al. Pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureter
30、al reflux in children. J Urol 1997;157(5):1846-1851. Garin EH et.al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006;117:626-632. Garin EH, Campos A, Homsy Y. Primary ve
31、sicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249-256.,References,Gordon I et.al. Primary vesicoureteral reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. J Am Soc Nephrol 2003;14:739-744. Gu
32、yatt GH et.al. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993;270:2598-2601. Guyatt GH et.al. How to use an article about therapy or prevention. B. What were the results and will they help me in caring for my patients? JAMA 1994;271:59-63. Lee RS
33、et.al. Antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis. Pediatrics 2006;118(2):586-593. Penido Silva JM et.al. Clinical course of prenatally detected primary vesicoureteral reflux. Pediatr Nephrol 2006;21:86-91. Schwab CW et.al. Spontaneous resolution of vesicoureteral
34、reflux: a 15-year perspective. J Urol 2002;168:2594-2599. Williams G et.al. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr 2001;138(6):868-874. Yu RN, Roth DR. Treatment of vesicoureteral reflux using endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer gel: initial experience in pediatric patients by a single surgeon. Pediatrics 2006;118(2):698-703.,
