A Splash of Color: Blue Blood

This case provides another interesting indication for the use of Methylene Blue:

The Problem

A transport team is called to a small critical access hospital in northern Michigan for a 59-year-old male. The patient had presented to the hospital from his primary care physician following a fall and subsequent injury to his right knee and left wrist. The patient’s past medical history (PMH) is significant for hypertension, Type II Diabetes and intravenous drug abuse. During his hospital course, the patient underwent arthroscopy to the right knee and incision & drainage to both the right knee and left wrist. Physicians overseeing his care also expressed concern about heart valve vegetation based upon his PMH and he was subsequently scheduled for a trans-esophageal echocardiogram (TEE). This revealed a normal ejection fraction (EF) without signs of endocarditis.

During the TEE the patient’s oxygen saturation (SpO₂) rapidly dropped and he became centrally cyanotic. Benzocaine-induced methemoglobinemia was suspected since this topical anesthetic was used liberally during the procedure. The patient was intubated, transferred to the intensive care unit (ICU) and transport to a tertiary care center was arranged.  

Upon arrival of the transport team, the patient’s SpO₂ was noted to be in the low 90% range. His initial Methemoglobin level was 41.6% (normal range is 0-3%). Because taking someone to altitude can naturally cause adverse effects on oxygenation and given the current marginal state of the patient’s SpO₂, the decision was made to attempt to treat the patient’s Methemoglobin prior to initiating transport. The treatment option of choice…Methylene Blue.

Some Background

Methemoglobin is an altered state of hemoglobin where the normal ferrous (Fe2+) molecule of iron is oxidized to a ferric (Fe3+) molecule. The altered state of the ferric (Fe3+) molecule is unable to bind with oxygen. Worse yet, the remaining ferrous (Fe2+) molecules have a higher affinity to oxygen causing a Left shift of the oxyhemoglobin dissociation curve resulting in impaired oxygen delivery to the tissues. Patients often initially present with cyanosis that does not respond to oxygen therapy, headache, tachycardia, and dyspnea. Symptoms can escalate to respiratory depression, cardiovascular collapse, seizures, and death.

Normally, our bodies naturally oxidize hemoglobin to methemoglobin at a slow rate which allows the reduction of methemoglobin back to functional hemoglobin. During homeostasis our bodies undergo this process naturally and the level of methemoglobin accounts for less than 1 percent of total hemoglobin. When Methemoglobin levels reach 1.5g/dL, approximately 8-12 percent of normal hemoglobin have been oxidized to Methemoglobin.

Methemoglobin can be due to congenital or acquired causes. While congenital causes are due to a deficiency in cytochrome b5 reductase or mutation in the alpha, beta, or gamma globulin gene; acquired methemoglobin is caused by certain chemicals and medications.

One common medication known for inducing Methemoglobinemia is the topical anesthetic Benzocaine. Benzocaine is used as a spray for sore throats or as a topical anesthetic for mouth pain or infant teething. Due to an increased incidence of Benzocaine induced Methemoglobinemia, the FDA issued a statement in 2011, and again in 2018, warning of the risks.

Methylene Blue Utilized to Treat Severe Methemoglobinemia

So how does Methylene Blue treat Methemoglobinemia? Methylene Blue was originally used as a dye in the textile industry and was quickly discovered to have medicinal properties in the 19th century. Due to its physicochemical properties, it has been used to treat malaria, psychosis, and bipolar disease. Recently it has been used to treat vasoplegia and Methemoglobinemia. Methylene Blue acts as an artificial electron transporter and ultimately reduces the Ferric (Fe3+) molecule to the normal functional Ferrous (Fe2+) molecule.

Methylene Blue is given intravenously in a dose of 1-2mg/kg over 5-30minutes. Evidence of the effectiveness of Methylene Blue in the reduction of the Ferric (Fe3+) molecule can be seen rapidly, often within one hour.

Pearls of administering Methylene Blue:

• Mix in D5W only
• Pulse oximeter may be unreliable due to an underestimation of the oxygen saturation reading
• Utilize co-oximetry to directly and accurately measure Methemoglobin levels
• May cause hypoglycemia

Back to the Case: Outcome

After administration of Methylene Blue (1.8mg/ml over 30 minutes), the patient’s SpO₂ was noted to decrease to 85% within 5 minutes. Anecdotally, this is known to happen due to the inaccuracy of the pulse oximeter in the setting of Methylene Blue administration. Within 15 minutes, his SpO₂ had increased to 97-100%. Patient transport was initiated and he remained hemodynamically stable during the 45 minute rotor-wing transport to the tertiary care center.

Take Home Points

• Kudos to the referring medical staff who rapidly intervened and recognized the need for care beyond their capabilities.
• Methemoglobinemia, while fairly uncommon, has some very distinct clinical manifestations requiring prompt management.
• Overall, Methylene Blue is an effective and rapid treatment to reduce the Ferric (Fe3+) to Ferrous (Fe2+) molecules in Methemoglobinemia.

References

FDA. (2018, May 22). FDA Drug Safety Communication: Reports of a rare, but serious and potentially fatal adverse effect with the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mouth. Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-reports-rare-serious-and-potentially-fatal-adverse-effect-use-over.

Journal of Psychosocial Nursing and Mental Health Services. 2016;54(9):21-24 https://doi.org/10.3928/02793695-20160818-01

Prchal MD, Josef. T. (2018, November 28). Clinical features, diagnosis, and treatment of methemoglobinemia. Retrieved from: https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatment-of-methemoglobinemia?search=methemoglobinemia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H2

Prchal MD, Josef. T. (2018, November 28). Medications and chemicals that may cause acquired methemoglobinemia. Retrieved from: https://www.uptodate.com/contents/image?imageKey=HEME%2F51406&topicKey=HEME%2F7094&search=methemoglobinemia&rank=1~150&source=see_link

UpToDate. Benzocaine: Drug information. Retrieved from:https://www.uptodate.com/contents/benzocaine-drug-information?search=benzocaine&source=search_result&selectedTitle=1~68&usage_type=panel&kp_tab=drug_general&display_rank=1#F139913

UpToDate. Methylene blue: Drug information. Retrieved from: https://www.uptodate.com/contents/methylene-blue-drug-information?search=methylene%20blue&source=search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F52867527