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PII: S0022-5347(18)43035-2
DOI: 10.1016/j.juro.2018.04.062
Reference: JURO 15568
Please cite this article as: Chew BH, Miller NL, Abbott JE, Lange D, Humphreys MR, Pais VM Jr, Monga
M, Krambeck AE, Sur RL, A Randomized Control Trial of Preoperative Prophylactic Antibiotics Prior to
Percutaneous Nephrolithotomy in Low Infectious Risk Population: A Report from the EDGE Consortium,
The Journal of Urology® (2018), doi: 10.1016/j.juro.2018.04.062.
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Ben H. Chew1,2, MD; Nicole L. Miller1,3, MD; Joel E. Abbott, DO4; Dirk Lange1,2, PhD;
Mitchell R. Humphreys1,5, MD; Vernon M. Pais Jr1,6, MD; Manoj Monga1,7, MD; Amy E.
Krambeck1,8, MD; Roger L. Sur1,9, MD
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Institutions:
1 – Member, EDGE Research Consortium, 2-The University of British Columbia,
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Vancouver, British Columbia, 3 - Vanderbilt University, Nashville, Tennessee, 4 –
Chesapeake Urology Associates, Hanover, Maryland, 5 - The Mayo Clinic Arizona,
Phoenix, Arizona 6 –Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire 7 –
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Cleveland Clinic, Cleveland, OH 8-Indiana University 9- University of California, San
Diego, California,
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Funding sources: The Project described was partially supported by the National
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Institutes of Health, Grant UL1TR001442 of CTSA, as well as UL1TR002377
(REDCap). The content is solely the responsibility of the authors and does not
necessarily represent the official views of the NIH.
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Running title:
Preoperative antibiotics prior to PCNL
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Abstract
Introduction
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percutaneous nephrolithotomy (PCNL). These studies are limited by lower quality
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standard definitions of sepsis. The American Urological Association (AUA) Best Practice
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Statement recommends <24 hours of IV antibiotics, but no other data exist about the
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CONSORT guidelines), multi-institutional trial to assess preoperative antibiotics in PCNL
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patients at low risk of developing infections.
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Methods
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cultures and without any urinary drains) undergoing PCNL were enrolled. Subjects were
randomized to nitrofurantoin 100 mg BID for 7 days preceding surgery (n=43) and
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control arm with no oral antibiotics (n=43). All subjects received peri-operative doses of
Results
treatment and control cohorts, (stone size 19mm and 17mm, p=0.47). Intra-operative
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different between the treatment and control groups (12% and 14%, 95% CI [-0.163,
0.122], p=1.0). Other infectious parameters and complications were similar (intensive
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care admission, fever, hypotension, leukocytosis).
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Conclusion
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Our study demonstrated no advantage to providing one week of preoperative oral
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antibiotics per AUA Best Practice Statement appears sufficient.
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Introduction
Sepsis is one of the most devastating complications following PCNL with rates reported
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antibiotics for this procedure based on numerous studies demonstrating mitigation of
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Recently, investigations have concluded there may be benefit to prolonged antecedent
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antibiotics.6, 7 These investigations reported 30% and 8% reduction in the risk of sepsis,
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respectively, leading to the suggestion that the use of prolonged pre-operative oral
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perioperative antibiotic use has been shown to produce few adverse antibiotic-related
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that threaten the internal validity of these studies and therefore potentially limit their
refute findings. Of note, SIRS is an acceptable surrogate for sepsis in that sepsis is
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kidney stone consortium of tertiary care centers (www.endoedge.org), hypothesized
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that prolonged pre-operative antibiotics would not reduce post-operative sepsis from
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PCNL. We therefore sought to determine if 7 days of pre-operative oral antibiotics
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PCNL in a prospective randomized trial.
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Methods
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This multicenter, prospective, randomized, single blind, superiority trial was conducted
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between January 2015 and July 2017 at 7 locations throughout the United States and
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institutional review board (IRB) (UC San Diego, University of British Columbia, Vanderbilt
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University, Mayo Clinic Arizona, Dartmouth Hitchcock, Cleveland Clinic, Mayo Clinic
Rochester, Indiana University), and participants provided written informed consent prior
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Harmonisation Guideline for Good Clinical Practice. UC San Diego (UCSD) served as the
principal investigating and study data safety monitoring regulating site. No protocol
investigator study person who provided each institution their randomization list to a
similar non-investigator person, who then disclosed allocation when requested by each
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site investigator.
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Eligible patients were enrolled through each institution’s urology outpatient clinics.
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Eligible patients included any person 18 years old or older with a renal calculus of any
size for which PCNL was recommended. Exclusion criteria were eGFR < 60 mL/min/1.73
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m2 or Glucose 6-phosphate dehydrogenase deficiency (G6PD) (both contraindications
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for nitrofurantoin); cirrhosis and/or hepatitis; pregnancy (urine test for pregnancy done
PCNL with the final day of prophylactic course being 1 day prior to surgery.
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acute uncomplicated urinary tract infections. Patients randomized to the control arm
received no preoperative antibiotic course. On the day of surgery, antibiotics were given
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to all patients (control and treatment arms)—a dose of ampicillin IV (2 g) and
gentamicin IV (5 mg/kg ideal body weight) within 120 minutes of surgery start time.
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Patients with a penicillin allergy received vancomycin IV (1 g) instead of ampicillin and
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patients with gentamicin/aminoglycoside allergy received ceftriaxone IV (2 g) instead of
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IV antibiotics. The macrobid prescription was written by a non-investigator member of
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the surgical team. The investigator and study team were blinded to treatment
independent person. The database was unlocked after the study at which point the
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Prone PCNL was then performed after access was obtained by either interventional
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radiology or the surgeon. Tracts were balloon dilated to 30Fr. Intracorporeal lithotripsy
performed as necessary. At time of surgery, urine from the renal pelvis, bladder urine,
and the stone itself were sent for culture. Renal drainage devices (ureteral stents,
Post-operatively, the patients were admitted to the hospital and monitored per usual
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clinical procedure. CBC and basic metabolic chemistry bloodwork was obtained on
postoperative day 1. Patients were discharged from the hospital per each institution’s
clinical protocol. After surgery, patients were followed in the clinic 1-12 weeks with
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imaging.
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Data Collection and Handling
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De-identified data was collected by each participating site and entered into a designated
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Data Analysis
The primary outcome was rate of postoperative sepsis and was compared between the
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intervention and control groups for the postoperative period with univariate and
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multivariate analysis. Sepsis was defined by the 2012 International Guidelines for
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Management of Severe Sepsis and Septic Shock12 where an infectious source (e.g.
kidney stone) and 2 or more of the following variables are temporally associated:
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temperature > 38.3 Celsius or < 36 Celsius, heart rate > 90/minute (at least 12 hours
after surgery), respiratory rate > 20/minute (at least 12 hours after surgery), altered
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mental status defined as lack of orientation to either name, place, or time/date, systolic
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blood pressure < 90 mmHg, mean arterial pressure < 70 mmHg, or systolic blood
pressure decrease > 40 mmHg, leucocyte count > 12000 or < 4000.
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complications. Descriptive statistics were used to analyze the data with mean, range for
medians and variance reported for continuous variables, and proportions reported for
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categorical variables. Using 2-sided P values, statistical significance was set at p≤0.05.
Sample Size of 80 patients (40 per each cohort) was calculated assuming β=0.20, α=0.05,
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with the power to detect a 30% reduction in sepsis rate based on prior literature.6 An
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intent-to-treat (ITT) analysis was performed and included all randomized patients who
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The null hypothesis assumed there was no difference in sepsis between one week of
antibiotic dose alone. SAS software was used for all statistical operations (SAS Institute
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Results
The study failed to reject the null hypothesis—i.e. there was no difference in rates of
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sepsis between treatment 12% and control 14% arms (mean difference -0.020 95% CI
[-0.163, 0.122], p=1.0). There were also no differences in the rates of septic shock (0%
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and 0%) or intensive care unit admission (treatment: 4.8% and control: 0%, p=0.24).
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for all other variables, nephrostomy tube placement following PCNL reduced the risk of
sepsis (OR=0.23, 95%CI [0.04, 0.91], p=0.049). Controlling for all variables, 1 week of
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antibiotics did not significantly reduced the risk of sepsis (OR=0.56, 95%CI [0.14, 2.2],
p=0.40)
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Of the 86 subjects randomized to intervention with nitrofurantoin (n=43) and control
(n=43), no subjects withdrew (Figure 1). Both baseline characteristics (Table 1) and
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intraoperative outcomes were essentially similar except control cohort had a larger
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proportion of nephrostomy tube use (Table 2).
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Furthermore, there was no multi-organ system failure in any subject. Leukocytosis was
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not different, with 11 (40% and 33%, p=0.64) between treatment and control,
differences either. Renal pelvis cultures were concordant with intraoperative bladder
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urine cultures in 49% and 63% of treatment and control patients, respectively (p=0.28).
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Stone cultures were concordant with intraoperative bladder urine cultures in 49% and
42%, p=0.37) or when sub-stratified for Clavien-Dindo grades (Table 3). Treatment
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cohort infectious related complications included the following: serum sickness from
pre-operative antibiotics; simple urinary tract infection requiring oral antibiotics; re-
urosepsis related to infected proximal ureteral fragment. See Table 4 for all
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Discussion
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AUA Best Practice Statement recommends < 24 hours of peri-operative antibiotics for
PCNL.4, 5 However, even with peri-operative antibiotics there is a risk of sepsis and the
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potential sequelae of septic shock with possible multi-organ dysfunction.2 Fortunately,
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the reported rates are low at 0.3-2.5%. Juxtaposed with this problem is the growing
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antibiotic stewardship is thought to contribute to increasing bacterial resistance.13 The
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recent patient deaths associated with carbapenam-resistant enterobacter speak to this
situation.14
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There is evidence that prolonged pre-operative antibiotics reduces the risk of sepsis
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week of oral ciprofloxacin reduced sepsis in patients with large stones and/or
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hydronephrosis.6 Yet these are the only two existing level 2b and 1b trials, respectively,
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that address this question. The former study is not a true prospective comparative trial
controlled trial should be done to further confirm these results.” The latter trial was a
single center RCT which could have benefited from alignment with CONSORT guidelines.
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Specific domains of concern include the following: outdated “sepsis” definition, which
did not include low body temperature < 36 Celsius, explicit hypotension definition or
change in mental status (see Appendix 1—CONSORT checklist item 6a); lack of sample
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size calculation but instead post hoc power calculation (not recommended by checklist
item 7a); lack of randomization list concealment (check list item 9) whereby
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investigators could potentially view the randomization list; it was unclear how cohorts
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were analyzed (intention to treat, per protocol, modified intention to treat [check list
item 12a]); and lack of flow diagram which clarifies loss of follow-up, disenrollment,
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missing outcomes (check list item 13a).
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The goal of our study was to conduct a rigorous Level 1b multi-center trial that would
define the right balance between judicious and sufficient peri-operative antibiotic
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prophylaxis. From this study we conclude that there was no reduced sepsis rate with
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prolonged pre-operative PCNL antibiotic use. Urosepsis and shock is thought to be due
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risk with prolonged surgery, degree of hydronephrosis (surrogate for bacterial load),
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bacterial load in the renal pelvis, and presence of large, infected stones.1, 15 From our
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data, the only predictors of sepsis appeared to be the lack of nephrostomy tube use
after PCNL (OR=0.23, 95% CI [0.04, 0.91], p=0.049). However, not only are the
confidence intervals wide but it should also be noted this analysis is potentially limited
by inadequate outcome variable size—i.e. for outcome events per variable values of less
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than 10-15 (in our case total sepsis events = 11), the regression coefficients can be
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How should our data be interpreted in light of two prior studies6, 7 suggesting that one
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undergoing PCNL with large stones and/or severely hydronephrotic kidneys? The
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nitrofurantoin study concluded that large stones necessitate prolonged antibiotics, yet
this was only seen on univariate analysis and not seen on multivariate analysis. They
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also concluded that hydronephrotic patients benefited from treatment; however,
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review of their methodology does not clarify what degree of hydronephrosis benefits
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ciprofloxacin study made similar conclusions but no formal inferential statistics were
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Although we did not find large stone size or hydronephrosis to be predictors of sepsis,
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we do think these findings from prior studies make intuitive sense. Large stones and
hydronephrosis appear to be suitable surrogate markers for bacterial load. Our average
axial stone size of 1.6 cm indicates our study was admittedly not enriched with large
stones. The Bag et al study suggested that females on multivariate analysis (OR=3.3)
were at increased risk of sepsis, though we did not see these findings.6 Additionally, our
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cases were all performed at high volume stone centers where operative time is often
under 2 hours (mean OR time 111 min) which decreases patients’ risk of sepsis. Lastly,
this trial is one of two that the EDGE consortium has performed with an ongoing trial
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targeting “moderate to high risk” PCNL patients—i.e. patients who have positive pre-
operative urine cultures, existing ureteral stents or nephrostomy tubes. This “moderate
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to high risk” cohort has yet to be evaluated with respect to appropriate duration of pre-
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operative antibiotics. We acknowledge the findings of the current trial should not be
applied to moderate-high risk PCNL patients until data is available. Moreover, we also
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caution over-generalization of this data as clinician’s judgement may justify a more
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liberal approach to antibiotic use.
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institutional setting which attempts to answer the controversy behind prolonged pre-
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operative antibiotics. For both the safety of PCNL patients in averting sepsis and for the
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ongoing attempt to balance judicious antibiotic use, we believe this study adds
to the AUA Best Practice Statement for only peri-operative antibiotics at time of PCNL.3
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Conclusions
antibiotics per AUA Best Practice Statement offer similar protection to one week of pre-
operative antibiotics against the occurrence of sepsis post PCNL . A study evaluating the
role of pre-operative antibiotics in cohorts at higher risk for infection is currently under
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way within this consortium.
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Figure 1: Flow Diagram of the progress through phases of randomized control trial as per
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CONSORT statement. AN
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References
1. O'Keeffe, N. K., Mortimer, A. J., Sambrook, P. A. et al, Severe sepsis following
percutaneous or endoscopic procedures for urinary tract stones. Br J Urol, 72:
277, 1993.
2. Segura, J. W., Endourology. J Urol, 132: 1079, 1984.
3. Wolf, J. S., Jr., Bennett, C. J., Dmochowski, R. R. et al, Urologic Surgery
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Antimicrobial Prophylaxis Best Practice Policy, P.: Best practice policy statement
on urologic surgery antimicrobial prophylaxis. J Urol, 179: 1379, 2008.
4. Charton, M., Vallancien, G., Veillon, B. et al, Urinary tract infection in
percutaneous surgery for renal calculi. J Urol, 135: 15, 1986.
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5. Darenkov, A. F., Derevianko, II, Martov, A. G. et al, [The prevention of infectious-
inflammatory complications in the postoperative period in percutaneous surgical
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interventions in patients with urolithiasis]. Urol Nefrol (Mosk): 24, 1994.
6. Bag, S., Kumar, S., Taneja, N. et al, One week of nitrofurantoin before
percutaneous nephrolithotomy significantly reduces upper tract infection and
urosepsis: a prospective controlled study. Urology, 77: 45, 2011.
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7. Mariappan, P., Smith, G., Moussa, S. A. et al, One week of ciprofloxacin before
percutaneous nephrolithotomy significantly reduces upper tract infection and
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urosepsis: a prospective controlled study. BJU Int, 98: 1075, 2006.
8. Lai, W. S., Assimos, D., The Role of Antibiotic Prophylaxis in Percutaneous
Nephrolithotomy. Rev Urol, 18: 10, 2016.
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international guidelines for management of severe sepsis and septic shock: 2012.
Crit Care Med, 41: 580, 2013.
13. Ventola, C. L., The antibiotic resistance crisis: part 1: causes and threats. P T, 40:
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277, 2015.
14. Garcia-Castillo, M., Garcia-Fernandez, S., Gomez-Gil, R. et al, Activity of
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Table 1. Patient demographics and stone characteristics (mean ± SD unless specified otherwise)
Group 1
(Control) Group 2 (NFT x p
Variable (n = 43) 1 week) (n = 43) value
Male (%) 26 (39.5%) 27 (37.2%) 1.0
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Age 62 56 0.23
Body mass index 31 ± 9.9 30 ± 7.0 0.59
ASA Score 2.5 2.3 0.11
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Max axial stone diameter (mm) (range) 18 (1.6-55) 16 (5.1-65) 0.70
Max longitudinal stone diameter (mm) (range) 17 (1.6-63) 19 (3.5-56) 0.81
Hounsfield units 892 910 0.82
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Skin-to-stone distance (cm) 9.6 9.9 0.78
Left (%) 22 (51%) 24(56%) 0.67
Hydronephrosis 31(72%) 37(88%) 0.10
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Stone surface area on axis (mm2) (range) 175 (0.45-2640) 202 (2.50-1973) 0.89
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--Upper pole supracostal, n (%) 7 (16.30%) 9 (20.90%) 0.78
--Upper pole subcostal, n (%) 5 (11.60%) 9 (20.90%) 0.38
--Middle kidney, n (%) 6 (14.00%) 6 (14.00%) 1.00
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--Lower pole, n (%) 28 (65.10%) 25 (58.10%) 0.66
Multiple acces tracts 3 (7.00%) 6 (14.30%) 0.31
Operative time (min) 108 ± 44 115 ± 47 0.50
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Estimated blood loss (mL) 133 ± 115 151 ± 177 0.58
Preop creatinine (mg/dL) 0.94 0.9 0.39
Postop creatinine (mg/dL) 1.03 0.95 0.22
Preop hemoglobin (g/dL) 14 15 0.28
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Postop hemoglobin (g/dL) 12 12 0.50
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Preop leukocyte count (109/L) 7.6 7.0 0.28
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Postop leukocyte count (10 /L) 11 11 0.82
Ureteral stent placed, n (%) 16 (37%) 20 (46%) 0.51
Nephrostomy tube placed, n (%) 29 (67%) 17 (40%) 0.02*
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Hypotension 5 (11%) 6 (14%) 0.76
Tachycardia (HR > 90 bpm) 13 (30%) 11 (26%) 0.81
Tachypnea (RR > 20 rpm) 11 (26%) 7 (17%) 0.43
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Elevated lactate 3 (12%) 0 (0.0%) 0.11
Elevated leukocyte count (> 12,000 WBC) 16 (40%) 13 (33%) 0.64
Received ABx for > 24 hours postop 7 (16%) 9 (21%) 0.59
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Positive intraop bladder urine culture 1 (2.3%) 1 (2.3%) 1.0
Positive intraop renal pelvis urine culture 1 (2.3%) 1 (2.3%) 1.0
Positive stone culture 4 (9.3%) 4 (9.3%) 1.0
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Positive postop bladder urine culture 0 (0.0%) 2 (4.7%) 0.49
Positive postop blood culture 0 (0.0%) 0 (0.0%) -
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Complications: none 30 (70%) 25 (58%) 0.37
--Clavien I 4 (9.3%) 8 (19%) 0.351
--Clavien II 5 (11%) 3 (7.0%) 0.71
--Clavien IIIA 1 (2.3%) 0 (0.0%) 1.00
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1 ER for SOB. CXR with atelectasis.
1 Nephrostomy tube in place for longer than usual
1 Surgical site hematoma. Resolved spontaneously
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1 SOB post-op. CXR with atelectasis
1 Post-op hypotension requiring bolus x2
1 Post-op apical pneumothorax. Resolved spontaneously
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2 Admitted for hydronephrosis after stent removed
2 Admitted for infection requiring IV antibiotics
2 Serum sickness 2/2 pre-op microbic
3B JJ stent malpositioned. Return to OR for stent change
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3B Urinary sepsis, obstructing UPJ stone requiring ureteroscopy
3B Residual obstructing stone with ureteroscopy POD #1
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Control Group (No Pre-op Antibiotics)
Clavien-Dindo Description
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Class
1 Return to ER with flank pain
1 Post-op flare in Parkinson’s disease
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2 Urinary sepsis
3A Re-admitted for hematuria. CT angiogram negative
3B Intra-operative bleeding -> early termination of case.
3B Hemothorax requiring chest tube, VATS, Decortication
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Abbreviations
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SIRS: systemic inflammatory response syndrome
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