From the Editor

Farewell to indigo carmine

OBG Manag. 2014 September;26(9):8, 9

With a nationwide shortage of this marker dye, what are the options, and cautions, for obstetricians and gynecologists?

References

1. Indigo carmine injection. American Society of Health-System Pharmacists (ASHP) Web site. http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=861. Updated July 29, 2014. Accessed August 21, 2014.

2. Lin BL, Iwata Y. Modified cystoscopy to evaluate unilateral traumatic injury of the ureter during pelvic surgery. Am J Obstet Gynecol. 1990;162(5):1343–1344.

3. Lee M, Sharifi R. Methylene blue versus indigo carmine. Urology. 1996;47(5):783–784.

4. Thompson JD. Operative injuries to the ureter: prevention, recognition and management. In Rock JA, Thompson JD, eds. TeLinde’s Operative Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins; 1997:1155.

5. Wang AC. The techniques of trocar insertion and intraoperative urethroscopy in tension-free vaginal taping: an experience of 600 cases. Acta Obstet Gynecol Scand. 2004;83(3):293–298.

6. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.

7. Shah-Khan MG, Lovely J, Degnim AC. Safety of methylene blue dye for lymphatic mapping in patients taking selective serotonin reuptake inhibitors. Am J Surg. 2012;204(5):798–799.

8. Ng BK, Cameron AJ. The role of methylene blue in serotonin syndrome: a systematic review. Psychosomatics. 2010;51(3):194–200.

9. Hui JY, Harvey MA, Johnston SL. Confirmation of ureteric patency during cystoscopy using phenazopyridine HCl: a low-cost approach. J Obstet Gynaecol Can. 2009;31(9):845–849.

10. Moore CR, Shirodkar SP, Avallone MA, et al. Intravesical methylene blue facilitates precise identification of the diverticular neck during robot-assisted laparoscopic bladder diverticulectomy. J Laparoendosc Adv Surg Tech A. 2012;22(5):492–495.

11. Mhaskar R, Mhaskar AM. Methemoglobinemia following chromopertubation in treated pelvic tuberculosis. Int J Gynaecol Obstet. 2002;77(1):41–42.

12. Rzymski P, Wozniak J, Opala T, Wilczak M, Sajdak S. Anaphylactic reaction to methylene blue dye after laparoscopic chromopertubation. Int J Gynaecol Obstet. 2003;81(1):71–72.

13. Dewachter P, Mouton-Faivre C, Trechot P, Lieu JC, Mertes PM. Severe anaphylactic shock with methylene blue instillation. Anesth Analg. 2005;101(1):149–150.

14. McFadyen I. The dangers of intra-amniotic methylene blue. Br J Obstet Gynaecol. 1992;99(2):89–90.

15. Van der Pol JG, Wolf H, Boer K, et al. Jejunal atresia related to the use of methylene blue in genetic amniocentesis in twins. Br J Obstet Gynaecol. 1992;99(2):141–143.

16. Kidd SA, Lancaster PA, Anderson JC, et al. Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenat Diagn. 1996;16(1):39–47.

17. Hobbins JC, Winsberg F, Blanchett M, et al. Section 5: fetal imaging. Prenat Diagn. 1981;1(5):35–38.

Suddenly, indigo carmine is in short supply throughout the United States. One manufacturer has stopped production because of a raw materials shortage; another is experiencing manufacturing delays. Neither company can estimate a resupply or product return date.¹

Indigo carmine is approved by the US Food and Drug Administration (FDA) to localize ureteral orifices during cystoscopy and is commonly used in obstetrics and gynecology as a marker dye in the following additional situations:

administered in a dilute solution via a catheter to back fill the bladder and test for bladder injury
administered via a cannula in the uterine cavity to test the patency of the fallopian tubes
injected into the amniotic fluid compartment to test for premature rupture of the membranes (PROM)
injected into the amniotic fluid of a twin gestation to mark the amniotic fluid of one twin.

With this agent in short supply, we need to identify alternative marker dyes to use in our clinical practice. In this editorial, I provide a list of possible options to replace indigo carmine. Evidence supporting the use and safety of marker dyes in obstetrics and gynecology is based on small cohorts or case reports. The available evidence is of modest to low quality, and it is especially challenging to identify uncommon adverse effects. Consequently, expert opinion guides most practice recommendations.

Options to test the function of the ureters at cystoscopy
Given the lack of availability of indigo carmine, I recommend one of the following three options to test the function of the ureters at cystoscopy.

Partially fill the bladder with a solution of either sterile water or a 10% dextrose solution. (Experienced surgeons may prefer to use saline.) The turbulence of the interaction between the ureteral urine jet and instilled fluid in the bladder may permit visualization of the urine stream exiting the ureteral orifices as it swirls through the sterile water or dextrose solution. Both sterile water and a 10% dextrose solution offer a contrast in viscosity between the urine and the cystoscopy fluid, which may enhance the ability to detect the urine jet leaving the ureter.²

Administer IV methylene blue. Methylene blue is FDA approved for methemoglobinemia treatment. For this indication, it is administered intravenously at a dose of 1 to 2 mg/kgover 5 to 10 minutes. Paradoxically, when administered at a dose of >7 mg/kg, methylene blue can cause methemoglobinemia.³

Methylene blue often is provided as a 1% solution of 10 mg/mL in 10-mL vials. To use intravenous (IV) methylene blue to test ureteral function at cystoscopy, administer IV methylene blue 50 mg over 5 minutes. Use the cystoscope to view the colored urine exiting the ureteral orifices.^4,5 Administering a small dose of IV furosemide may accelerate the appearance of methylene blue in the urine.

When to use caution. Methylene blue blocks serotonin metabolism by inhibiting monoamine oxidase and may precipitate a serotonin syndrome in patients taking selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs).

Common findings in the serotonin syndrome include: temperature above 38° C (100.4° F), anxiety, agitation, delirium, clonus, tremor, and hypertonia.⁶ I recommend that you DO NOT use IV methylene blue in patients taking these medications.^7,8

Great caution should be used before administering IV methylene blue in the presence of the following clinical situations:

renal impairment
G6PD deficiency
pediatric patients.

Methylene blue never should be given by a subcutaneous or intrathecal route. In pregnant women it should never be injected into the amniotic fluid compartment.

Use preoperative oral phenazo-pyridine. If the preoperative plan includes a cystoscopy procedure to test ureteral function, administering oral phenazopyridine in the preoperative holding area will result in colorization of the urine within 30 minutes, and it will persist for approximately 4 to 5 hours. To use this approach, administer one dose of phenazopyridine (Pyridium, Azo-Gesic), 100 mg or 200 mg orally, 30 minutes to 1 hour before the planned surgical start time, in the preoperative holding area.⁹ During cystoscopy, the urine from the ureteral jet will be colored orange.

When to use caution. Phenazopyridine should not be administered to patients with G6PD deficiency.

Option to test for bladder injury
Methylene blue. If methylene blue is used to test the integrity of the bladder, I recommend diluting 10 mg methylene blue in 1 L normal saline and then instilling the dilute solution through a catheter into the bladder.¹⁰

It is unlikely that this technique will be associated with sufficient methylene blue absorption to cause a serotonin syndrome. Therefore, this technique can be used in patients taking SSRIs, SNRIs, and MAOIs.