Effectiveness of Assessing Ureteral Patency Using Preoperative Phenazopyridine

The rate of urinary tract injury at the time of gynecologic surgery in various studies ranges from 0.6% to 11% depending on the procedure. 1 , 2 , 3 , 4 Given this, intraoperative cystoscopy is often used to assess integrity of the bladder and ureters and has been shown to increase detection rates of lower urinary tract injuries. 1 , 5 Previously, visualization of ureteral jets was aided by intravenous administration of indigo carmine. However, unavailability of this medication since 2014 has necessitated exploration of alternative methods for assessing ureteral patency at the time of cystoscopy. One medication that has emerged as potentially useful for cystoscopic assessment of ureteral flow is phenazopyridine (Pyridium – Gemini laboratories, Bridgewater, NJ), which stains the urine a dark orange. Since 2014, our institution has adopted the practice of administering preoperative oral phenazopyridine as we routinely perform intraoperative cystoscopy at the time of most major gynecologic surgeries, including hysterectomies of all routes. However, at the beginning of this study, there was little data regarding the efficacy of phenazopyridine in such clinical scenarios, particularly in the general gynecology literature. This is especially true given poorly defined pharmacokinetic properties with subsequently unpredictable excretion times, as well as unknown utility in patients with compromised renal function. 6 , 7 The goal of our study was to determine the efficacy of preoperative phenazopyridine in assessing ureteral patency during gynecologic surgery. Secondarily, we sought to identify factors associated with the efficacy of preoperative phenazopyridine use in this clinical setting.

We identified 482 patients who underwent cystoscopy during gynecologic surgery at our institution between January 2014 and July 2016. Of those, 207 patients met inclusion criteria; 275 patients were excluded because they either did not receive phenazopyridine (N= 123) or underwent cystoscopy solely for reasons other than evaluation of ureteral patency following gynecological surgery (N= 152). During the early study period leading up to the national shortage of indigocarmine, there were 42 patients who received indigocarmine, 42 patients who received methylene blue and 13 patients who received no agent to aid detection of detect ureteral patency. Following December of 2014, none of our patient received indigocarmine and phenazopyridine became the predominant agent given for cystoscopy to assess ureteral patency. There were 25 patients who did not receive phenazopyridine after December 2014 (4 methylene blue, 7 sodium fluorescein, 14 no agent). Of the two hundred and six patients received pre-operative oral phenazopyridine (either 100mg or 200mg) on the morning of scheduled surgery. One patient received 200mg of phenazopyridine the night before surgery. Demographic data, indication for surgery and type of surgery is found in Table 1 . Surgical indications included pelvic floor disorders, gynecologic malignancy or premalignancy, symptomatic fibroid uterus or abnormal uterine bleeding, and chronic pelvic pain. The surgeries were performed by Urogynecology in 72 cases (35%) and Gynecology or Gynecologic Oncology in 135 cases (65%). Of 207 patients, 190 needed only preoperative phenazopyridine to confirm ureteral flow, corresponding to 91.8% efficacy [ Table 2 ]. Two urinary tract injuries – one cystotomy and one ureteral ligation during a vaginal hysterectomy – were identified with use of preoperative phenazopyridine alone. The ureteral ligation was confirmed intraoperatively with a retrograde pyelogram. The other 17 patients (8.2%) required intraoperative sodium fluorescein because phenazopyridine was ineffective in identifying flow in either of the ureters [ Table 2 ]. Sodium fluorescein given intraoperatively at the time of cystoscopy was effective in 15 (88%) of these patients. The remaining two patients had other abnormalities (one had “sluggish” ureteral flow, the other had a history of a reimplanted ureter) that required additional interventions (intravenous pyelogram and intraoperative urology consult, respectively) to visualize the ureteral flow. Neither had intraoperative urinary tract injuries. Univariate analysis of potential factors that might be associated with reduced effectiveness of phenazopyridine were analyzed by comparing the phenazopyridine effective and ineffective groups. A 200mg versus 100mg phenazopyridine dose (p = 0.0224) and lower intraoperative urine output (median 450mL vs 800mL, p = 0.0023) were statistically significant factors associated with phenazopyridine success. Longer time between phenazopyridine administration and surgical end time trended towards an association with phenazopyridine efficacy, but was not statistically significant (0.1419). The other factors were not significant, including phenazopyridine to surgery start time. To control for potential confounding factors, multivariable analysis was performed including factors that trended towards significance with a p value < 0.25 from univariate analysis [ Table 4 ]. Factors included in the model were patient age, phenazopyridine dose, intraoperative urine output, phenazopyridine to surgery end time, intraoperative urine output, operating room net fluid, phenazopyridine to surgery time. Phenazopyridine doses were considered to select the best logistic regression model for phenazopyridine failure using stepwise selection. Multivariate analysis revealed that a lower dose of phenazopyridine was associated with increased phenazopyridine failure. The odds of phenazopyridine failure decrease by 70% when using a phenazopyridine dose of 200mg versus 100mg. Similarly, increased urine output was statistically significant increased risk of phenazopyridine failure. For every 100 mL increase in intraoperative urine output, the odds of phenazopyridine failure increased by 10%. Finally, there was a trend towards decreased phenazopyridine failure with increased time between the phenazopyridine administration and the end of surgery. For every 10 minutes increase in time from phenazopyridine administration to the surgery end time, the odds of phenazopyridine failure decreased by 4%. In summary, phenazopyridine is highly effective in detecting ureteral flow, but becomes less effective when a lower dose is given or when the urine is more dilute. Phenazopyridine appears to be less effective when given close to the surgery start time. We did not have any patients with phenazopyridine failure when phenazopyridine was given at least 4.5 hour prior to surgery start time. We encountered 2 (0.97%) intraoperative injuries and that both of these injuries were detected with phenazopyridine alone. There were no delayed urinary tract injuries in the study population after a mean follow-up of 125 days. Additionally, there were no differences in adverse events between the two groups.

This trial shows that phenazopyridine is effective for intraoperative evaluation of ureteral patency and identification of urinary tract injury. Its efficacy can be improved by administration of 200mg rather than 100mg of phenazopyridine preoperatively at least 4.5 hours prior to surgery. Successful visualization of ureteral flow is correlated with lower intraoperative UOP, likely secondary to less dilute urine. Phenazopyridine use does not impede use of additional interventions (sodium fluorescein or intravenous pyelogram) when needed for further ureteric assessment and can be used effectively by all obstetrician-gynecologists, regardless of level of training.

After IRB approval was obtained, a retrospective review was performed on all women undergoing cystoscopy performed by surgeons in the Department of Obstetrics and Gynecology at Olive View-UCLA Medical Center, a Los Angeles County teaching hospital in northern Los Angeles, from January 1, 2014 until July 31, 2016. We chose this time period to ensure inclusion of all patients who received preoperative phenazopyridine prompted by the indigo carmine shortage in June of 2014. Consecutive patients were identified via review of departmental surgical case logs identifying all patients who underwent cystoscopy during the study period. Only patients who underwent cystoscopy with the goal to identify ureteral patency as part of a larger gynecological surgery were included in the study. Patients were excluded if they did not receive phenazopyridine or underwent cystoscopy solely for other reasons, such as evaluation of microscopic hematuria, isolated mid-urethral sling placement, or cervical cancer staging. Patient charts, operative reports, and medication administration records were reviewed. Patients were included if they underwent cystoscopy and had received a preoperative dose of phenazopyridine within twenty-four hours of the cystoscopy. Review of the medical administration records in the electronic health record was performed to confirm for each case that the patient actually took the phenazopyridine, the dose and time of drug administration. Phenazopyridine was given as a single 100 mg or 200 mg dose at provider discretion. Demographic data including age, race, body mass index (BMI), parity, American Society of Anesthesia (ASA) classification score, preoperative diagnosis, surgical procedure, renal function via serum creatinine and glomerular filtration rate were recorded. Nursing notes, operative reports, discharge summaries, and clinic postoperative visit notes were reviewed to determine the time and dose given of the preoperative phenazopyridine, the intraoperative intravenous fluids given, the estimated blood loss, the intraoperative urine output for the entire procedure (as we did not have the exact timing of the cystoscopy), administration and timing of additional agents for evaluation of ureteral flow (i.e. sodium fluorescein, methylene blue), and intraoperative or postoperative complications that occurred up to six weeks postoperatively. There was not official protocol for what to do if phenazopyridine was ineffective, and alternative medications or procedures were selected per provider preference. To verify that sodium fluorescein had not been given, we cross checked our data with a pharmacy audit. Because of the retrospective nature of this study, we were unable to determine the exact time of intraoperative cystoscopy. Instead we used the surgery end time as a surrogate marker as it is our typical practice to perform our cystoscopies at the end of the case. During uterosacral ligament vaginal vault suspensions, we perform cystoscopy after placing the suspension sutures and again after suspending the vaginal vault, the latter of which occurs near the end of the surgery. If a patient underwent more than one cystoscopy during the surgery, the last cystoscopy was the only one included in this study. Descriptive analysis was used to characterize the patient population. Phenazopyridine effectiveness was derived by comparing two cohorts of patients: a phenazopyridine effective and a phenazopyridine ineffective group. Differences between the groups were tested with Fisher’s exact tests for categorical values and Wilcoxon tests for continuous values. Factors studied in univariate analysis for association with phenazopyridine effectiveness included age, race, gravity, parity, American Society of Anesthesia (ASA) classification score, height, weight, body mass index, serum creatinine, glomerular filtration rate, phenazopyridine dose, preoperative diagnosis, primary surgical procedure, intraoperative intravenous fluids, estimated blood loss, intraoperative urine output, net intraoperative fluid status, time from phenazopyridine dose to end of surgery and complications. Factors found to be significant by univariate analysis at the P ≤ 0.25 significance level were tested using multivariate regression models.