Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Evaluation of Ureteral Patency in the Post-indigo Carmine Era

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02677623
Recruitment Status : Completed
First Posted : February 9, 2016
Results First Posted : May 30, 2019
Last Update Posted : May 30, 2019
Sponsor:
Information provided by (Responsible Party):
Columbia University

Tracking Information
First Submitted Date  ICMJE February 4, 2016
First Posted Date  ICMJE February 9, 2016
Results First Submitted Date  ICMJE March 27, 2019
Results First Posted Date  ICMJE May 30, 2019
Last Update Posted Date May 30, 2019
Study Start Date  ICMJE March 2015
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
Visual Analog Scale (VAS) [ Time Frame: Intraoperative ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: February 4, 2016)
Visual Analog Scale (VAS) [ Time Frame: Intraoperative ]
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. The study team later measures the mark on the 10 cm line using a ruler to determine the number score.
Change History Complete list of historical versions of study NCT02677623 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of Ureteral Patency in the Post-indigo Carmine Era
Official Title  ICMJE Evaluation of Ureteral Patency in the Post-indigo Carmine Era
Brief Summary

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.

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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Ureteral Patency
Intervention  ICMJE
  • Drug: Pyridium
  • Drug: Sodium Fluorescein
  • Drug: Mannitol
  • Other: Normal Saline
Study Arms  ICMJE
  • 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
    Intervention: 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
    Intervention: 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
    Intervention: Drug: Mannitol
  • Experimental: Control- Normal saline
    • Method of administration: irrigant during cystoscopy
    • Dose: 300cc
    • Known adverse events: no known significant adverse events
    • Contraindications: none
    Intervention: Other: Normal Saline
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 8, 2017)
140
Original Estimated Enrollment  ICMJE
 (submitted: February 4, 2016)
137
Actual Study Completion Date  ICMJE August 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02677623
Other Study ID Numbers  ICMJE AAAP3450
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Cara Grimes, MD Columbia University
PRS Account Columbia University
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP