Evaluation of Ureteral Patency in the Post-indigo Carmine Era

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.

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