What are alternate intravenous (IV) dyes for cystoscopy post-hysterectomy with the unavailability of indigo carmine and fluorescein?

What are alternate intravenous (IV) dyes for cystoscopy post-hysterectomy with the unavailability of indigo carmine and fluorescein?

Comment by InpharmD Researcher

Available data suggest oral and injectable products such as indocyanine green, 5-aminolevulinic acid, phenazopyridine, and vitamin B12 as potential alternatives to indigo carmine. Fluorescein has been compared, either directly or indirectly, to oral phenazopyridine, dextrose, mannitol, and normal saline primarily to assess ureteral patency in surgical settings. Therapeutic equivalence among suggested agents to either indigo carmine or fluorescein is inconclusive, given the lack of direct comparative data.

Background

For gynecologic surgical procedures or cystoscopies, a number of fluorescent dyes have been described. Indigo carmine (indigotin-disulfonate sodium) was the original dye used for fluorescence visualization but suffered from multiple drug shortages since its inception, sparking investigations into alternative agents. These include oral and injectable products such as methylene blue, indocyanine green, 5-aminolevulinic acid, fluorescein, phenazopyridine, and vitamin B12. Other clinical trials that directly compared with fluorescein included oral phenazopyridine, dextrose, mannitol, and normal saline. [1], [2], [3], [4]

A 2015 retrospective study (N= 25 patients who collectively underwent 26 robot-assisted ureteral reconstructions) evaluated intraurethrally injected indocyanine green with subsequent visualization under near-infrared fluorescence over a follow-up of 12 months. No indocyanine green-associated perioperative complications were reported. All procedures were deemed clinically and radiologically successful, though a small sample size severely limits this study.
To prepare indocyanine green, 25 mg of sterile IC-Green (Akorn Inc., Lake Forest, USA) was dissolved in 10 ml of distilled water upon patient arrival in the operating room. A 6F ureteral catheter was inserted into the diseased ureter; then retrograde pyelography was performed to localize the stricture. The 10 ml indocyanine green solution was injected into the ureteral catheter into the lumen, above and below the level of stenosis, immediately followed by clamping of the ureteral catheter and subsequent securing of the ureteral catheter to the Foley catheter, left to remain in the surgical field. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What are alternate intravenous (IV) dyes for cystoscopy post-hysterectomy with the unavailability of indigo carmine and fluorescein?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Evaluating Ureteral patency in the Post-Indigo Carmine Era: A Randomized Controlled Trial
Design	Randomized, controlled, open-label trial N= 130
Objective	To compare surgeon satisfaction with four methods of evaluating ureteral patency during cystoscopy at the time of benign gynecologic or pelvic reconstructive surgery: oral phenazopyridine, intravenous sodium fluorescein, mannitol bladder distention, and normal saline bladder distention
Study Groups	Phenazopyridine (n= 33) Sodium fluorescein (n= 32) Mannitol (n= 32) Normal saline (n= 33)
Inclusion Criteria	Age 18 years or older, undergoing scheduled elective gynecologic or urogynecological surgery
Exclusion Criteria	Pregnancy, known urologic anatomical anomaly, history of adverse reaction or contraindication to treatment
Methods	Patients were randomized to receive phenazopyridine 200 mg PO, sodium fluorescein 25 mg intravenous (IV), mannitol 1000 mL 20% infusion, and normal saline. Neither the surgeons nor the operation team were blinded to the fluorescent agent used. The operation team was assessed immediately after surgery based on 6 100-mm visual analog scales (VAS) indicating satisfaction, ease of evaluation of ureters, visualization, and global satisfaction. Adverse events were evaluated post-operatively.
Duration	Up to 6-weeks post-operative visit
Outcome Measures	Primary: assessment of surgeon satisfaction on 100-mm VAS Secondary: ease of evaluation, visualization, would use routinely, all based on 100-mm VAS
Baseline Characteristics		Phenazopyridine (n= 33)	Sodium fluorescein (n= 32)	Mannitol (n= 32)	Normal saline (n= 33)
	Age, years	52	48	50	52
	Body mass index, kg/m²	30	31	28	28
	Type of surgery Abdominal Laparoscopic Robotic Vaginal Pelvic reconstruction	1 3 8 2 16	2 6 10 5 7	4 3 12 3 9	1 10 9 3 8
Results	Endpoint	Phenazopyridine (n= 33)	Sodium fluorescein (n= 32)	Mannitol (n= 32)	Normal Saline (n= 33)	p-Value
	Surgeon satisfaction, mm	48	20	0	28	< 0.001
	Ease of evaluation, mm	35	21	0	17	< 0.001
	Visualization Urethral jets Bladder mucosa Urethra	22.5 38.5 15.5	19 36 18	0 0 0	34 4 4	< 0.001 < 0.001 < 0.001
	Surgeon would use this method routinely, mm	52	30	0	36	< 0.001
Adverse Events	Intra-operative adverse events did not differ between groups. A patient that received 500 mg of sodium fluorescein developed transient yellowing of the sclera.
Study Author Conclusions	The use of mannitol during cystoscopy to assess ureteral patency provided surgeons with the most overall satisfaction, ease of use, and superior visualization without affecting surgery or cystoscopy times. There were no differences in adverse events, including the incidence of urinary tract infections.
InpharmD Researcher Critique	Treatment was unblinded to the surgeons, which introduces significant bias. There were notable low instances of bladder and urethral injuries leading to surgical procedures and the type of surgery varied between groups.

References:

Grimes CL, Patankar S, Ryntz T, et al. Evaluating ureteral patency in the post-indigo carmine era: a randomized controlled trial. Am J Obstet Gynecol. 2017;217(5):601.e1-601.e10. doi:10.1016/j.ajog.2017.07.012

Intraoperative Cystoscopic Evaluation of Ureteral Patency: A Randomized Controlled Trial
Design	Multicenter, randomized, controlled trial N= 176
Objective	To compare different modalities to aid in the evaluation of intraoperative ureteral patency on cystoscopy in the postindigo carmine era
Study Groups	Dextrose 10% (n= 44) Phenazopyridine (n= 44) Fluorescein (n= 44) Saline (n= 44)
Inclusion Criteria	Patients aged 18 years or older, undergoing gynecologic or urogynecological surgery in which a routine cystoscopy was planned
Exclusion Criteria	Underlying chronic kidney disease, renal anomaly, ureteral stent in place, contraindications to interventions like allergies
Methods	Patients were randomized to receive either dextrose 10% solution as bladder distention media, 200 mg oral phenazopyridine administered 30 minutes prior to cystoscopy, 50 mg intravenous (IV) fluorescein, or saline placebo. Surgeons were asked to rate satisfaction and confidence of the assessment of ureteral patency. Surgeons were not blinded to fluoroescence used.
Duration	6 weeks
Outcome Measures	Primary: ureteral jet visibility Secondary: satisfaction-confidence score by surgeons of each agent.
Baseline Characteristics		Dextrose 10% (n= 44)	Phenazopyridine (n= 44)	Fluorescein (n= 44)	Saline (n= 44)
	Age, years	59.3	60.0	60.3	63.2
	Parity	2	2	2	2
	Body mass index, kg/m²	26.9	30.3	26.7	26.4
	Surgery time, min	102	133	105	106
Results	Endpoint	Dextrose 10% (n= 44)	Phenazopyridine (n= 44)	Fluorescein (n= 44)	Saline (n= 44)	p-Value
	Ureteral jet visibility	Data was primarily presented as a graph. When compared to saline, dextrose 10% and sodium fluorescein were found to have a statistically significant difference (p= 0.004 and p< 0.001, respectively). Phenazopyridine was not statistically beneficial.
	Satisfaction-confidence score	Data was primarily presented as a graph. Similar to above, dextrose 10% and sodium fluorescein reported statistically significant high satisfaction-confidence scores while saline and phenazopyridine were lower.
	UTI	29.5%	20.5%	22.7%	22.7%	0.80
	Acute urinary retention	50%	38.6%	54.5%	50%	0.65
	Time of cystoscopy, min	2	3	3	3	0.11
Study Author Conclusions	Compared with the control, 10% dextrose and sodium fluorescein resulted in improved visibility and provided significantly more satisfaction in the evaluation for ureteral patency with no considerable increase in operative time or morbidity.
InpharmD Researcher Critique	While dextrose 10% may be a viable alternative to fluorescein, they were not directly compared. Oral phenazopyridine proved to be inadequate in this trial when compared to saline.

References:

Espaillat-Rijo L, Siff L, Alas AN, et al. Intraoperative Cystoscopic Evaluation of Ureteral Patency: A Randomized Controlled Trial. Obstet Gynecol. 2016;128(6):1378-1383. doi:10.1097/AOG.0000000000001750