Evaluation of Ureteral Patency in the Post-indigo Carmine Era

Many gynecologic, urologic and pelvic reconstructive surgeries require accurate ways to identify the opening of the ureters to ensure that they are working correctly. Historically, indigo carmine, an intravenous medication that dyes the urine blue, has been used to help visualize the opening of the ureters with cystoscopy which is a camera placed inside the bladder. In June 2014, the FDA announced there was current shortage of indigo carmine. Thus, investigators need to evaluate other methods for assessing ureteral patency. Ideal alternatives are agents that are low-risk, inexpensive, provide comparable visualization, are readily available and are easy to use.

Examples of such agents currently being used to evaluate the ureters, include oral pyridium, IV sodium fluorescein, and mannitol. These agents help identify the opening of the ureters by either dyeing the urine a different color such as pyridium and sodium fluorescein, or by having a different viscosity to urine such as mannitol. This study will compare three methods of evaluating ureteral patency at time of cystoscopy compared to no method: mannitol, sodium fluorescein, and pyridium.

Study Overview

• Status: Completed
• Conditions: Ureteral Patency
• Intervention / Treatment: Drug: Mannitol; Other: Normal Saline; Drug: Pyridium; Drug: Sodium Fluorescein

Detailed Description

Many gynecologic, urologic and pelvic reconstructive surgeries require accurate intra-operative evaluation of ureteral patency. Numerous studies show that cystoscopy detects a greater proportion of bladder and ureteral injuries than visual inspection alone.The rate of ureteral injury in gynecologic surgery ranges from 0.6 to 11% when discovered on routine intraoperative cystoscopy depending on the procedure. In a review by Gilmour et al, the incidence of bladder injury in studies performing routine cystoscopy was 4-fold higher than those studies that did not. Early recognition of injury and repair during the primary surgery most often results in less morbidity for the patient, more successful outcome, and increased ease of repair.

Cystourethroscopy is a surgical procedure in which a fiberoptic endoscope is introduced through the urethra to examine the entire lumen of the urethra and bladder for diseases or abnormalities in a systematic manner.There are numerous indications for diagnostic cystourethroscopy during gynecologic surgery. The most important indications are to rule out cystotomy and intravesical or intraurethral suture or mesh placement, verify bilateral ureteral jets to ensure patency, and evaluate a suspected urine leak during or after laparotomy, laparoscopy or vaginal surgery.

Historically, indigo carmine, indigotindisulfonate sodium has been used to assist with cystourethroscopy. Ureteral function is assessed by visualization of ureteral efflux of blue dye after the intravenous injection of indigo carmine. Indigo carmine has many advantages. These include no known drug interactions or metabolites, easy dosing of 40mg or 5 to 10 cc of 0.8% solution, changing urine to a non-physiologic blue color that eases visualization and the ability to give the medication intravenously immediately prior to the procedure. In patients with normal renal function and adequate hydration, the dye is visible after approximately ten minutes, having a half-life of four to five minutes. Because of its large molecular size, it is largely excreted rather than reabsorbed. There are few contraindications to use of indigo carmine. It should be used with caution in patients with cardiovascular diseases secondary to its mild pressor effect.

The U.S. Food and Drug Administration announced the current shortage of indigotindisulfonate sodium in June 2014. This is due to the inability to obtain the active agent. There are two suppliers of indigo carmine in the United States: Akron and American Regent. Akron has discontinued manufacturing indigo carmine with no plan to resume production. American Regent plans to continue manufacturing indigo carmine based on component availability.

Methylene blue is an alternative to indigo carmine. Like indigo carmine, it can be given intravenously. However, it does have some risks. Methylene blue is variably metabolized to multiple end products but is largely metabolized to leukomethylene, which is colorless and therefore, may not be visualized in the urine. It cannot be used in pregnant patients and those with glucose-6-phosphate dehydrogenase deficiency because of risk of inducing hemolytic anemia. It may also cause methemoglobinemia when given in high doses greater than 7mg/kg. Lastly, methylene blue is a monoamine oxidase inhibitor and can cause serotonin syndrome in patients taking other serotonergic agents.

Given the shortage of indigo carmine and the risks associated with use of methylene blue, investigators need to evaluate other methods for assessing ureteral patency. Ideal alternatives are agents that are low-risk, inexpensive, provide comparable visualization, are readily available, and are easy to use. Preoperative oral phenazopyridine and intravenous urelle and sodium fluorescein are other agents that can dye the urine. The use and safety profile of oral phenazopyridine as a bladder analgesic is well established when used for a single short course. Within one hour after ingestion, the urine acquires a characteristic orange tint. A recent study by Hui et al showed that bilateral ureteral patency and bladder mucosal integrity was confirmed in all cases of 124 women that received oral phenazopyridine prior to pelvic surgery. Phenazopyridine is a safe, inexpensive dye that assists effectively in the confirmation of ureteric patency when cystoscopy is planned during pelvic surgery. Consistent with the literature, pyridium has been used at our institution for visualization of the ureters. Some reported concerns include obscuring of the bladder mucosa and a striking similarity between bloody ureteral efflux and pyridium-dyed urine that can be alarming intra-operatively. Doyle et al used sodium fluorescein as an alternative to indigo carmine to assess ureteral patency. This study found that ten percent sodium fluorescein given intravenously in doses ranging from 0.25 to 1.0 cc results in good visualization of ureteral jets. Sodium fluorescein injections have been routinely used for retinal angiography using significantly higher doses than cystoscopy requires. They have proven to be safe and cost effective. A prospective study measuring adverse reactions in patients undergoing ophthalmic angiography found the most common reactions to be nausea (2.9%), vomiting (1.2%) and flushing or rash (0.5%).Mannitol is a low-viscosity, isotonic distending media that is commonly used during hysteroscopy. As the viscosity is different than that of urine, it may allow for better visualization of the flow of urine during cystoscopy. It provides excellent visibility for the endoscopic surgeon but also possesses properties that have a potential impact on patient safety. Five percent mannitol is typically used during transurethral resection or hysteroscopy. Excess mannitol absorption has been known to cause hyponatremia; however, this is an uncommon event. The severity of hyponatremia is directly related to the volume of irrigation fluid that is retained. Absorption greater than 1000mL is typically required to cause clinically significant hyponatremia. In this study, investigators will use only 300mL of mannitol to distend the bladder. Therefore, the risk of hyponatremia is minimal.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

- Planned cystoscopy

Exclusion Criteria:

1. Women who are pregnant

2. Women with contraindications to pyridium, sodium fluorescein or mannitol:

   1. Intra-operative administration of nitric oxide, prilocaine and sodium nitrite
   2. Anuria
   3. Women with creatinine greater than 1 or Cr Cl < 50ml/minute
   4. Known allergy to pyridium, sodium fluorescein or mannitol.
3. Women with a known urologic anatomical anomaly

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A- Pyridium; Method of administration: oral; Dose: 200 mg PO with small sip of water; Known adverse events: yellow discoloration of skin or sclera, 1-10% central nervous system effects including headache and dizziness, GI effect of cramping, < 1% acute renal failure, methemoglobinemia, hemolytic anemia, hepatitis, rash, skin pigmentation, vertigo, stomach cramps; Contraindications: to be used in caution in patients with renal impairment Cr Cl < 50ml/minute and in patients who are receiving nitric oxide, prilocaine and sodium nitrite as it can cause methemoglobinemia	Drug: Pyridium
Experimental: B- Sodium Fluorescein; Method of administration: intravenous; Dose: 25 mg; Known adverse events: nausea, vomiting, flushing or rash, hypersensitivity and anaphylactic reactions can occur following injection and immediate treatment with epinephrine should be available, skin and urine discoloration (urine may appear bright yellow for 24-36 hours), extravasation may cause skin sloughing, toxic neuritis and phlebitis, nausea, rare cardiac arrest and seizure,; Contraindications: use with caution in patients with history of hypersensitivity, allergies or asthma	Drug: Sodium Fluorescein
Experimental: C- Mannitol; Method of administration: irrigant during cystoscopy; Dose: 300cc during cystoscopy to visualize the ureters; Known adverse events: dysuria, polyuria, hyponatremia with excess absorption, potential increased risk of urinary tract infection; Contraindications when used as a genitourinary irrigation solution: anuria	Drug: Mannitol
Experimental: Control- Normal saline; Method of administration: irrigant during cystoscopy; Dose: 300cc; Known adverse events: no known significant adverse events; Contraindications: none	Other: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale (VAS)	This is a 10-cm visual analog scale to determine which method of evaluating ureteral patency is most satisfactory to physicians. The smiley face is at one end and the frowning face is at the other end. Smiling is 1 and frowning is 10. The scale is completed by surgeon, anesthesiologist and the circulator by placing an "x" or a "mark" anywhere on the 10 cm line towards how good and or bad each person felt about the of process of patency assessment that was used. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the "no pain" anchor and the patient's mark, providing a range of scores from a minimum of 0 to a maximum of 100. A higher score indicates greater pain intensity (worse outcome).	Intraoperative

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Cara Grimes, MD, Columbia University

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: February 4, 2016
• First Submitted That Met QC Criteria: February 4, 2016
• First Posted (Estimate): February 9, 2016

Study Record Updates

• Last Update Posted (Actual): May 30, 2019
• Last Update Submitted That Met QC Criteria: May 6, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: AAAP3450

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No