Hypersensitivity Reaction With Methylene Blue: A Rare Case

Author Information

Khadke B*, Koshewara P**, Gupta A S***

(* Junior Resident, ** Senior Resident, *** Professor, Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)


Methylene blue associated anaphylactic reaction is rare. We are presenting a 25 year old nulliparous patient, who suffered from acute hypersensitivity reaction with 1% methylene blue dye during tubal patency test. Importance of awareness about the entity, early detection of symptoms, its management, and its possible outcomes are presented here.


Methylene blue is methylthioninium chloride. It is commonly used as a dye in diagnostic procedures such as detection of fistula and for patency of fallopian tubes; it can also produce methemoglobinemia in susceptible individuals.[1] Methylene blue dye hypersensitivity reaction is commonly associated with dyspnea, precordial pain, restlessness, and apprehension, while tremor, hemolytic anemia, pulmonary edema, and even death can be associated with its anaphylactic reaction. Patients suffering from Glucose-6-phosphate dehydrogenase (G6PD) deficiency may produce methemoglobinemia when methylene blue dye is used because of their inability to reduce methylene blue to leukomethylene blue, hence use of methylene blue dye should be avoided in such patients.[2]

Case Report

A 25 year old nulliparous lady, married for 5 years presented to outpatient department with complaints of something coming out per vaginum for 2 years. She had one abortion two years prior and was anxious to conceive. The mass per vaginum aggravated on coughing, sneezing and straining at stools. Her medical & surgical history was unremarkable. On further evaluation, there was no history of asthma, allergies or any drug hypersensitivity reaction. On examination, her vital parameters were stable, systemic examination was within normal limits and clinical examination was suggestive of second degree uterine prolapse. Investigations were sent and anesthetic evaluation was performed. She was scheduled for abdominal sling surgery (Khanna’s sling) and assessment for infertility.
As is usual practice, prior to the day of surgery, a test dose of injection amoxycillin and clavulanic acid and injection xylocaine was performed and there was no allergic reaction observed. For surgical prophylaxis injection amoxycillin and clavulanic acid 1.2 g, injection metronidazole 500 mg and injection gentamycin 80 mg intravenously were administered. Spinal anesthesia was induced with injection bupivacaine that was given for subarachnoid block, and intravenously injections of 1 mg midazolam and 30 mg fentanyl were given for sedation.
Tubal patency evaluation was done through a trans cervical injection of 40 ml of methylene blue dye via a Leech Wilkinson’s cannula. The methylene blue dye was injected transcervically prior to the preparation of the abdomen and thighs with povidone iodine. To start with she was catheterized and then the vagina was painted with povidone iodine and as it was a second degree prolapse the Leech Wilkinson’s cannula was easily attached and transcervically the methylene blue dye 40 ml was injected. Presence of the dye in the peritoneal cavity and blue discoloration of the entire fallopian tubes seen on subsequent opening of the peritoneal cavity was the end point to be used to determine tubal patency. Soon after transcervical injection of methylene blue dye eruption of rash and urticarial wheals on the abdomen and thighs were noted. A possible anaphylactic reaction alert was sounded. At that point of time her heart rate was 92 beats per minute and blood pressure was 100/60 mm Hg, and her chest was clear bilaterally. Her oxygen saturation was 100% on nasal oxygen. Immediately, intravenously hydrocortisone 100 mg and injection dexamethasone 4 mg were administered. This resulted in slight reduction of the erythematous wheals over the abdomen. Other parts of the body were also examined, and no other allergic site was found. After 15 minutes she was reevaluated. There were no further allergic phenomena and her vitals parameters remained stable. Abdomen from xiphisternum to the knee was scrubbed, prepared and painted with povidone iodine scrub and solution after she stabilized from her urticaria. Khanna’s sling surgery was performed uneventfully and methylene blue dye indicating patent tubes was seen in the pelvic and peritoneum cavity. Her subsequent post-operative period was uneventful.


Methylene blue reaction is an IgE mediated reaction.[3] The immediate manifestations of IgE mediated reaction include urticaria, and rashes, accounting for more than 70% of the cases. Skin manifestations are the most common manifestations.[4] Spillage into the peritoneal cavity may have resulted in the urticaria occurring on the abdominal wall. Lymphatic and intravascular extravasation fortunately did not occur (uterus and fallopian tubes did not show any evidence of extravasation of the dye ) or was minimal or else a more severe reaction was possible. In this case, she developed an allergic reaction, which was unlikely due to any intravenous medication, because the urticarial eruptions noticed were localized to the abdomen and thighs only and were not generalized. Also, antibiotic and anesthetic drugs sensitivity test were done one day prior to the surgery; and these had tested negative for any allergic reactions. The time period between injection of methylene blue and the occurrence of reaction, and the location of the rash indicate the inciting agent to be methylene blue. Abdomen from xiphisternum to the knee was scrubbed, prepared and painted after the patient stabilized from her urticaria hence this excludes the reaction caused by local antiseptics. Even though very few cases of allergic reactions are observed with antiseptics some authors have reported anaphylactic reactions with povidone iodine as well as with chlorhexidine and these are also mentioned in the US FDA safety guidelines.[5,6] Prompt identification and systemic medications (corticosteroids) probably led to prevention of a severe reaction, or systemic effects.
A similar case was reported by Milio et al, wherein a 30 year old woman with primary infertility who under went laparoscopic chromopertubation with methylene blue dye  developed fatal pulmonary edema.[1] Another case of chromopertubation with use of methylene blue dye was reported by Bilgin et al in a woman with G6PD deficiency which precipitated the methemoglobinemia.[2]
Dewachter et al stated that, severe immunoglobulin E-mediated hypersensitivity reaction is associated with the use of 1% methylene blue for detection of tubal patency even under anesthesia. This requires the need for systematic investigation of potentially allergenic drugs and substances administered during the perioperative period.[3] Breast cancer surgery had been abandoned when a woman developed angioedema and urticaria on injection of methylene blue dye to detect the sentinel lymph node.[7] In our case she also developed urticaria and rash, but it was manageable with antihistaminic drug and steroid and surgery could be completed successfully.
In 1996, Trikha et al observed that, injection of methylene blue resulted in development of pulmonary oedema in an ASA grade-1 patient with change in patient oxygen saturation.[8] However, fortunately our case was non-severe and respiratory system was unaffected throughout the procedure. Similar case of pulmonary edema following laparoscopic chromopertubation with methylene blue was reported by Cm V et al.[9] The cardinal allergic sign and symptoms of tachypnoea and hypotension were found, which required immediate intervention with steroids, inotropes and intensive unit care while our patient was stable after administration of steroids and did not require any intensive care.
According to standardized procedures as recommended by the French Society of Anesthesiology and Critical Care Medicine, sensitivity test with methylene blue can be done preoperatively and to confirm methylene blue hypersensitivity. In vitro leucocytes histamine tests can also be done for the same purpose.[3] As the average incidence of reactions to blue colored dyes can range from 7 patients in 10, 000 to 2.7 patients per 100 it is difficult to say whether a policy/ guideline to do sensitivity test for all patients who will need to use these vital blue dyes be recommended. However, methylene blue has the best safety profile amongst all the vital blue dyes.


Although methylene blue dye is used commonly in many diagnostic procedures, hypersensitivity reaction to methylene blue should always be kept in to mind. Although it is rare, awareness about its occurrence is key to early diagnosis and management.

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Khadke B, Koshewara P, Gupta AS. Hypersensitivity reaction with methylene blue: A rare case. JPGO 2018. Volume 5 No.12. Available from: https://www.jpgo.org/2018/12/hypersensitivity-reaction-with.html